Journal articles on the topic 'Amyloid beta-protein Pathophysiology'
To see the other types of publications on this topic, follow the link: Amyloid beta-protein Pathophysiology.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Amyloid beta-protein Pathophysiology.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Ma, Chen, Fenfang Hong, and Shulong Yang. "Amyloidosis in Alzheimer’s Disease: Pathogeny, Etiology, and Related Therapeutic Directions." Molecules 27, no. 4 (February 11, 2022): 1210. http://dx.doi.org/10.3390/molecules27041210.
Full textAbstract:
The amyloid hypothesis of Alzheimer’s disease has long been the predominant theory, suggesting that Alzheimer’s disease is caused by the accumulation of amyloid beta protein (Aβ) in the brain, leading to neuronal toxicity in the central nervous system (CNS). Because of breakthroughs in molecular medicine, the amyloid pathway is thought to be central to the pathophysiology of Alzheimer’s disease (AD). Currently, it is believed that altered biochemistry of the Aβ cycle remains a central biological feature of AD and is a promising target for treatment. This review provides an overview of the process of amyloid formation, explaining the transition from amyloid precursor protein to amyloid beta protein. Moreover, we also reveal the relationship between autophagy, cerebral blood flow, ACHE, expression of LRP1, and amyloidosis. In addition, we discuss the detailed pathogenesis of amyloidosis, including oxidative damage, tau protein, NFTs, and neuronal damage. Finally, we list some ways to treat AD in terms of decreasing the accumulation of Aβ in the brain.
2
Alasmari, Fawaz, Musaad A. Alshammari, Abdullah F. Alasmari, Wael A. Alanazi, and Khalid Alhazzani. "Neuroinflammatory Cytokines Induce Amyloid Beta Neurotoxicity through Modulating Amyloid Precursor Protein Levels/Metabolism." BioMed Research International 2018 (October 25, 2018): 1–8. http://dx.doi.org/10.1155/2018/3087475.
Full textAbstract:
Neuroinflammation has been observed in association with neurodegenerative diseases including Alzheimer’s disease (AD). In particular, a positive correlation has been documented between neuroinflammatory cytokine release and the progression of the AD, which suggests these cytokines are involved in AD pathophysiology. A histological hallmark of the AD is the presence of beta-amyloid (Aβ) plaques and tau neurofibrillary tangles. Beta-amyloid is generated by the sequential cleavage of beta (β) and gamma (γ) sites in the amyloid precursor protein (APP) by β- and γ-secretase enzymes and its accumulation can result from either a decreased Aβ clearance or increased metabolism of APP. Previous studies reported that neuroinflammatory cytokines reduce the efflux transport of Aβ, leading to elevated Aβ concentrations in the brain. However, less is known about the effects of neuroinflammatory mediators on APP expression and metabolism. In this article, we review the modulatory role of neuroinflammatory cytokines on APP expression and metabolism, including their effects on β- and γ-secretase enzymes.
3
Gatti, Laura, Francesca Tinelli, Emma Scelzo, Francesco Arioli, Giuseppe Di Fede, Laura Obici, Leonardo Pantoni, et al. "Understanding the Pathophysiology of Cerebral Amyloid Angiopathy." International Journal of Molecular Sciences 21, no. 10 (May 13, 2020): 3435. http://dx.doi.org/10.3390/ijms21103435.
Full textAbstract:
Cerebral amyloid angiopathy (CAA), one of the main types of cerebral small vessel disease, is a major cause of spontaneous intracerebral haemorrhage and an important contributor to cognitive decline in elderly patients. Despite the number of experimental in vitro studies and animal models, the pathophysiology of CAA is still largely unknown. Although several pathogenic mechanisms including an unbalance between production and clearance of amyloid beta (Aβ) protein as well as ‘the prion hypothesis’ have been invoked as possible disease triggers, they do not explain completely the disease pathogenesis. This incomplete disease knowledge limits the implementation of treatments able to prevent or halt the clinical progression. The continuous increase of CAA patients makes imperative the development of suitable experimental in vitro or animal models to identify disease biomarkers and new pharmacological treatments that could be administered in the early disease stages to prevent irreversible changes and disease progression.
4
Carbone, Manuel Glauco, Giovanni Pagni, Claudia Tagliarini, Donatella Marazziti, and Nunzio Pomara. "Platelet APP Processing: Is It a Tool to Explore the Pathophysiology of Alzheimer’s Disease? A Systematic Review." Life 11, no. 8 (July 26, 2021): 750. http://dx.doi.org/10.3390/life11080750.
Full textAbstract:
The processing of the amyloid precursor protein (APP) is a critical event in the formation of amyloid plaques. Platelets contain most of the enzymatic machinery required for APP processing and correlates of intracerebral abnormalities have been demonstrated in platelets of patients with AD. The goal of the present paper was to analyze studies exploring platelet APP metabolism in Alzheimer’s disease patients trying to assess potential reliable peripheral biomarkers, to offer new therapeutic solutions and to understand the pathophysiology of the AD. According to the PRISMA guidelines, we performed a systematic review through the PubMed database up to June 2020 with the search terms: “((((((APP) OR Amyloid Precursor Protein) OR AbetaPP) OR Beta Amyloid) OR Amyloid Beta) OR APP-processing) AND platelet”. Thirty-two studies were included in this systematic review. The papers included are analytic observational studies, namely twenty-nine cross sectional studies and three longitudinal studies, specifically prospective cohort study. The studies converge in an almost unitary way in affirming that subjects with AD show changes in APP processing compared to healthy age-matched controls. However, the problem of the specificity and sensitivity of these biomarkers is still at issue and would deserve to be deepened in future studies.
5
LAGUNES, TERESA, MARISOL HERRERA-RIVERO, MARÍA ELENA HERNÁNDEZ-AGUILAR, and GONZALO E. ARANDA-ABREU. "Abeta(1-42) induces abnormal alternative splicing of tau exons 2/3 in NGF-induced PC12 cells." Anais da Academia Brasileira de Ciências 86, no. 4 (December 2014): 1927–34. http://dx.doi.org/10.1590/0001-3765201420130333.
Full textAbstract:
Protein tau plays a pivotal role in the pathophysiology of Alzheimer's disease, where its hyperphos-phorylation promotes aggregation and microtubule destabilization. Tau undergoes alternative splicing which generates six isoforms in the human brain, due to inclusion/exclusion of exons 2, 3 and 10. Dysregulation of the splicing process of tau exon 10 is sufficient to cause tauopathy and has shown to be influenced by beta-amyloid peptides, but splicing of other exons is less studied. We studied the effects of beta-amyloid(42) in the alternative splicing of tau exons 2/3 and 6, using untreated and Nerve Growth Factor-induced PC12 cells. Beta-amyloid exposure caused formed cell processes to retract in differentiated cells and altered the expression of exons 2/3 in both undifferentiated and differentiated cells. Expression of exon 6 was repressed in undifferentiated cells only. Our results suggest that beta-amyloid interferes with the splicing process of exons 2/3, favoring their exclusion and thus the expression of immature tau isoforms that are less efficient in stabilizing microtubules and may also be more prone to hyperphosphorylation. The molecular mechanism for this amyloid-tau interaction remains to be determined, but may have potential implications for the understanding of the underlying neuropathological processes in Alzheimer's disease.
6
Koike, Haruki, Yohei Iguchi, Kentaro Sahashi, and Masahisa Katsuno. "Significance of Oligomeric and Fibrillar Species in Amyloidosis: Insights into Pathophysiology and Treatment." Molecules 26, no. 16 (August 22, 2021): 5091. http://dx.doi.org/10.3390/molecules26165091.
Full textAbstract:
Amyloidosis is a term referring to a group of various protein-misfolding diseases wherein normally soluble proteins form aggregates as insoluble amyloid fibrils. How, or whether, amyloid fibrils contribute to tissue damage in amyloidosis has been the topic of debate. In vitro studies have demonstrated the appearance of small globular oligomeric species during the incubation of amyloid beta peptide (Aβ). Nerve biopsy specimens from patients with systemic amyloidosis have suggested that globular structures similar to Aβ oligomers were generated from amorphous electron-dense materials and later developed into mature amyloid fibrils. Schwann cells adjacent to amyloid fibrils become atrophic and degenerative, suggesting that the direct tissue damage induced by amyloid fibrils plays an important role in systemic amyloidosis. In contrast, there is increasing evidence that oligomers, rather than amyloid fibrils, are responsible for cell death in neurodegenerative diseases, particularly Alzheimer’s disease. Disease-modifying therapies based on the pathophysiology of amyloidosis have now become available. Aducanumab, a human monoclonal antibody against the aggregated form of Aβ, was recently approved for Alzheimer’s disease, and other monoclonal antibodies, including gantenerumab, solanezumab, and lecanemab, could also be up for approval. As many other agents for amyloidosis will be developed in the future, studies to develop sensitive clinical scales for identifying improvement and markers that can act as surrogates for clinical scales should be conducted.
7
Hultman, Karin, Sidney Strickland, and Erin H. Norris. "The APOE ε4/ε4 Genotype Potentiates Vascular Fibrin(Ogen) Deposition in Amyloid-Laden Vessels in the Brains of Alzheimer's Disease Patients." Journal of Cerebral Blood Flow & Metabolism 33, no. 8 (May 8, 2013): 1251–58. http://dx.doi.org/10.1038/jcbfm.2013.76.
Full textAbstract:
Evidence indicates a critical role for cerebrovascular dysfunction in Alzheimer's disease (AD) pathophysiology. We have shown that fibrin(ogen), the principal blood-clotting protein, is deposited in the AD neurovasculature and interacts with beta-amyloid (Ab), resulting in increased formation of blood clots. As apolipoprotein E (ApoE), a lipid-transporting protein with three human isoforms (E2, E3, and E4), also binds to Aβ, we hypothesized that ApoE and fibrin(ogen) may have a combined effect on the vascular pathophysiology in AD. We assessed whether APOE genotype differentially influences vascular fibrin(ogen) deposition in postmortem brain tissue using immunohistochemistry. An increased deposition of fibrin(ogen) was observed in AD cases compared with non-demented controls, and there was a strong correlation between cerebral amyloid angiopathy (CAA) severity and fibrin(ogen) deposition. Moreover, brains from AD cases homozygous for APOE ε4 showed increased deposition of fibrin(ogen), specifically in CAA- and oligomeric Aβ-positive vessels compared with AD APOE ε2 and ε3 allele carriers, an effect that was not directly linked to CAA severity and cerebrovascular atherosclerosis. These data further support a role for fibrin(ogen) in AD pathophysiology and link the APOE ε4/ε4 genotype with increased thrombosis and/or impaired fibrinolysis in the human AD brain.
8
Besli, Nail, and Guven Yenmis. "Assessment of the Interaction of Aggregatin Protein with Amyloid-Beta (Aβ) at the Molecular Level via In Silico Analysis." Acta Chimica Slovenica 67, no. 4 (December 15, 2020): 1262–72. http://dx.doi.org/10.17344/acsi.2020.6175.
Full textAbstract:
Alzheimer’s disease is a major neurodegenerative illness whose prevalence is increasing worldwide but the molecular mechanism remains unclear. There is some scientific evidence that the molecular complexity of Alzheimer’s pathophysiology is associated with the formation of extracellular amyloid-beta plaques in the brain. A novel cross- phenotype association analysis of imaging genetics reported a brain atrophy susceptibility gene, namely FAM222A and the protein Aggregatin encoded by FAM222A interacts with amyloid-beta (Aβ)-peptide (1-42) through its N-terminal Aβ binding domain and facilitates Aβ aggregation. The function of Aggregatin protein is unknown, and its three-dimensional structure has not been analyzed experimentally yet. Our goal was to investigate the interaction of Aggregatin with Aβ in detail by in silico analysis, including the 3D structure prediction analysis of Aggregatin protein by homology modeling. Our analysis verified the interaction of the C-terminal domain of model protein with the N-terminal domain of Aβ. This is the first attempt to demonstrate the interaction of Aggregatin with the Aβ. These results confirmed in vitro and in vivo study reports claiming FAM222A helping to ease the aggregating of the Aβ-peptide.
9
Katsinelos, Taxiarchis, Michael Doulberis, Stergios A. Polyzos, Apostolis Papaefthymiou, Panagiotis Katsinelos, and Jannis Kountouras. "Molecular Links Between Alzheimer's Disease and Gastrointestinal Microbiota: Emphasis on Helicobacter pylori Infection Involvement." Current Molecular Medicine 20, no. 1 (December 13, 2019): 3–12. http://dx.doi.org/10.2174/1566524019666190917125917.
Full textAbstract:
Alzheimer's disease (AD) is a neurodegenerative disease and the main form of dementia, characterized by progressive cognitive decline and detrimental consequences in both personal-family and global level. Within this narrative review, we provide recent molecular aspects of Tau, a microtubule AD-associated protein, as well as amyloid beta, involved in AD pathophysiology. Moreover, we provide additional emerging data from basic research as well as clinical studies indicating an implicating role of gastrointestinal microbiota (GI-M), including Helicobacter pylori infection (Hp-I), in AD pathophysiology. Likewise, we identified through a molecular prism the current evidence of AD pathogenesis as well as its linkage with GI-M and emphasizing the role of Hp-I. All in all, additional large-scale studies are required for the further clarification of AD pathophysiology and its connection with GI-M and Hp-I, so as novel therapies on molecular basis become available.
10
Kulas, Joshua A., Kendra L. Puig, and Colin K. Combs. "Amyloid precursor protein in pancreatic islets." Journal of Endocrinology 235, no. 1 (October 2017): 49–67. http://dx.doi.org/10.1530/joe-17-0122.
Full textAbstract:
The amyloid precursor protein (APP) has been extensively investigated for its role in the production of amyloid beta (Aβ), a plaque-forming peptide in Alzheimer’s disease (AD). Epidemiological evidence suggests type 2 diabetes is a risk factor for AD. The pancreas is an essential regulator of blood glucose levels through the secretion of the hormones insulin and glucagon. Pancreatic dysfunction is a well-characterized consequence of type 1 and type 2 diabetes. In this study, we have examined the expression and processing of pancreatic APP to test the hypothesis that APP may play a role in pancreatic function and the pathophysiology of diabetes. Our data demonstrate the presence of APP within the pancreas, including pancreatic islets in both mouse and human samples. Additionally, we report that the APP/PS1 mouse model of AD overexpresses APP within pancreatic islets, although this did not result in detectable levels of Aβ. We compared whole pancreas and islet culture lysates by Western blot from C57BL/6 (WT), APP−/− and APP/PS1 mice and observed APP-dependent differences in the total protein levels of GLUT4, IDE and BACE2. Immunohistochemistry for BACE2 detected high levels in pancreatic α cells. Additionally, both mouse and human islets processed APP to release sAPP into cell culture media. Moreover, sAPP stimulated insulin but not glucagon secretion from islet cultures. We conclude that APP and its metabolites are capable of influencing the basic physiology of the pancreas, possibly through the release of sAPP acting in an autocrine or paracrine manner.
11
Vidyanti, Amelia Nur, Jia-Yu Hsieh, Kun-Ju Lin, Yao-Ching Fang, Ismail Setyopranoto, and Chaur-Jong Hu. "Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion." International Journal of Molecular Sciences 21, no. 6 (March 21, 2020): 2176. http://dx.doi.org/10.3390/ijms21062176.
Full textAbstract:
The pathophysiology of vascular cognitive impairment (VCI) is associated with chronic cerebral hypoperfusion (CCH). Increased high-mobility group box protein 1 (HMGB1), a nonhistone protein involved in injury and inflammation, has been established in the acute phase of CCH. However, the role of HMGB1 in the chronic phase of CCH remains unclear. We developed a novel animal model of CCH with a modified bilateral common carotid artery occlusion (BCCAO) in C57BL/6 mice. Cerebral blood flow (CBF) reduction, the expression of HMGB1 and its proinflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β, and IL-6), and brain pathology were assessed. Furthermore, we evaluated the effect of HMGB1 suppression through bilateral intrahippocampus injection with the CRISPR/Cas9 knockout plasmid. Three months after CCH induction, CBF decreased to 30–50% with significant cognitive decline in BCCAO mice. The 7T-aMRI showed hippocampal atrophy, but amyloid positron imaging tomography showed nonsignificant amyloid-beta accumulation. Increased levels of HMGB1, TNF-α, IL-1β, and IL-6 were observed 3 months after BCCAO. HMGB1 suppression with CRISPR/Cas9 knockout plasmid restored TNF-α, IL-1β, and IL-6 and attenuated hippocampal atrophy and cognitive decline. We believe that HMGB1 plays a pivotal role in CCH-induced VCI pathophysiology and can be a potential therapeutic target of VCI.
12
Pal, Swadesh, and Roderick Melnik. "Coupled Neural–Glial Dynamics and the Role of Astrocytes in Alzheimer’s Disease." Mathematical and Computational Applications 27, no. 3 (April 21, 2022): 33. http://dx.doi.org/10.3390/mca27030033.
Full textAbstract:
Neurodegenerative diseases such as Alzheimer’s (AD) are associated with the propagation and aggregation of toxic proteins. In the case of AD, it was Alzheimer himself who showed the importance of both amyloid beta (Aβ) plaques and tau protein neurofibrillary tangles (NFTs) in what he called the “disease of forgetfulness”. The amyloid beta forms extracellular aggregates and plaques, whereas tau proteins are intracellular proteins that stabilize axons by cross-linking microtubules that can form largely messy tangles. On the other hand, astrocytes and microglial cells constantly clear these plaques and NFTs from the brain. Astrocytes transport nutrients from the blood to neurons. Activated astrocytes produce monocyte chemoattractant protein-1 (MCP-1), which attracts anti-inflammatory macrophages and clears Aβ. At the same time, the microglia cells are poorly phagocytic for Aβ compared to proinflammatory and anti-inflammatory macrophages. In addition to such distinctive neuropathological features of AD as amyloid beta and tau proteins, neuroinflammation has to be brought into the picture as well. Taking advantage of a coupled mathematical modelling framework, we formulate a network model, accounting for the coupling between neurons and astroglia and integrating all three main neuropathological features with the brain connectome data. We provide details on the coupled dynamics involving cytokines, astrocytes, and microglia. Further, we apply the tumour necrosis factor alpha (TNF-α) inhibitor and anti-Aβ drug and analyze their influence on the brain cells, suggesting conditions under which the drug can prevent cell damage. The important role of astrocytes and TNF-α inhibitors in AD pathophysiology is emphasized, along with potentially promising pathways for developing new AD therapies.
13
Modarresi, Farzaneh, Mohammad Ali Faghihi, Nikunj S. Patel, Barbara G. Sahagan, Claes Wahlestedt, and Miguel A. Lopez-Toledano. "Knockdown of BACE1-AS Nonprotein-Coding Transcript Modulates Beta-Amyloid-Related Hippocampal Neurogenesis." International Journal of Alzheimer's Disease 2011 (2011): 1–11. http://dx.doi.org/10.4061/2011/929042.
Full textAbstract:
Background. Alzheimer's disease (AD) is a devastating neurological disorder and the main cause of dementia in the elderly population worldwide. Adult neurogenesis appears to be upregulated very early in AD pathogenesis in response to some specific aggregates of beta-amyloid (Aβ) peptides, exhausting the neuronal stem cell pools in the brain. Previously, we characterized a conserved nonprotein-coding antisense transcript forβ-secretase-1 (BACE1), a critical enzyme in AD pathophysiology. We showed that the BACE1-antisense transcript (BACE1-AS) is markedly upregulated in brain samples from AD patients and promotes the stability of the (sense) BACE1 transcript. In the current paper, we examine the relationship between BACE1, BACE1-AS, adult neurogenesis markers, and amyloid plaque formation in amyloid precursor protein (APP) transgenic mice (Tg-19959) of various ages.Results. Consistent with previous publications in other APP overexpressing mouse models, we found adult neurogenesis markers to be noticeably upregulated in Tg-19959 mice very early in the development of the disease. Knockdown of either one of BACE1 or BACE1-AS transcripts by continuous infusion of locked nucleic acid- (LNA-) modified siRNAs into the third ventricle over the period of two weeks caused concordant downregulation of both transcripts in Tg-19959 mice. Downregulation of BACE1 mRNA was followed by reduction of BACE1 protein and insoluble Aβ. Modulation of BACE1 and BACE1-AS transcripts also altered oligomeric Aβaggregation pattern, which was in turn associated with an increase in neurogenesis markers at the RNA and protein level.Conclusion. We found alterations in the RNA and protein concentrations of several adult neurogenesis markers, as well as non-protein-coding BACE1-AS transcripts, in parallel with the course ofβ-amyloid synthesis and aggregation in the brain of Tg15999 mice. In addition, by knocking down BACE1 or BACE1-AS (thereby reducing Aβproduction and plaque deposition), we were able to modulate expression of these neurogenesis markers. Our findings suggest a distortion of adult neurogenesis that is associated with Aβproduction very early in amyloid pathogenesis. We believe that these alterations, at the molecular level, could prove useful as novel therapeutic targets and/or as early biomarkers of AD.
14
Matei, Nathanael, Sophie Leahy, Norman P. Blair, James Burford, Mansour Rahimi, and Mahnaz Shahidi. "Retinal Vascular Physiology Biomarkers in a 5XFAD Mouse Model of Alzheimer’s Disease." Cells 11, no. 15 (August 4, 2022): 2413. http://dx.doi.org/10.3390/cells11152413.
Full textAbstract:
Background: Alzheimer’s disease (AD) is a neurodegenerative disorder that affects the brain and retina and lacks reliable biomarkers for early diagnosis. As amyloid beta (Aβ) manifestations emerge prior to clinical symptoms and plaques of amyloid may cause vascular damage, identification of retinal vascular biomarkers may improve knowledge of AD pathophysiology and potentially serve as therapeutic targets. The purpose of the current study was to test the hypothesis that retinal hemodynamic and oxygen metrics are altered in 5XFAD mice. Methods: Thirty-two male mice were evaluated at 3 months of age: sixteen 5XFAD transgenic and sixteen wild-type mice. Spectral-domain optical coherence tomography, vascular oxygen tension, and blood flow imaging were performed in one eye of each mouse. After imaging, the imaged and fellow retinal tissues were submitted for histological sectioning and amyloid protein analysis, respectively. Protein analysis was also performed on the brain tissues. Results: Retinal physiological changes in venous diameter and blood velocity, arterial and venous oxygen contents, coupled with anatomical alterations in the thickness of retinal cell layers were detected in 5XFAD mice. Moreover, an increase in Aβ42 levels in both the retina and brain tissues was observed in 5XFAD mice. Significant changes in retinal oxygen delivery, metabolism, or extraction fraction were not detected. Based on compiled data from both groups, arterial oxygen content was inversely related to venous blood velocity and nerve fiber/ganglion cell layer thickness. Conclusions: Concurrent alterations in retinal hemodynamic and oxygen metrics, thickness, and tissue Aβ42 protein levels in 5XFAD mice at 3 months of age corresponded to previously reported findings in human AD. Overall, these results suggest that this mouse model can be utilized for studying pathophysiology of AD and evaluating potential therapies.
15
Maarouf, Chera L., Tyler A. Kokjohn, Charisse M. Whiteside, MiMi P. Macias, Walter M. Kalback, Marwan N. Sabbagh, Thomas G. Beach, Robert Vassar, and Alex E. Roher. "Molecular Differences and Similarities between Alzheimer's Disease and the 5XFAD Transgenic Mouse Model of Amyloidosis." Biochemistry Insights 6 (January 2013): BCI.S13025. http://dx.doi.org/10.4137/bci.s13025.
Full textAbstract:
Transgenic (Tg) mouse models of Alzheimer's disease (AD) have been extensively used to study the pathophysiology of this dementia and to test the efficacy of drugs to treat AD. The 5XFAD Tg mouse, which contains two presenilin-1 and three amyloid precursor protein (APP) mutations, was designed to rapidly recapitulate a portion of the pathologic alterations present in human AD. APP and its proteolytic peptides, as well as apolipoprotein E and endogenous mouse tau, were investigated in the 5XFAD mice at 3 months, 6 months, and 9 months. AD and nondemented subjects were used as a frame of reference. APP, amyloid-beta (Aβ) peptides, APP C-terminal fragments (CT99, CT83, AICD), β-site APP-cleaving enzyme, and APLP1 substantially increased with age in the brains of 5XFAD mice. Endogenous mouse tau did not show age-related differences. The rapid synthesis of Aβ and its impact on neuronal loss and neuroinflammation make the 5XFAD mice a desirable paradigm to model AD.
16
Namme, Jannatun Nayem, Asim Kumar Bepari, and Hirohide Takebayashi. "Cofilin Signaling in the CNS Physiology and Neurodegeneration." International Journal of Molecular Sciences 22, no. 19 (October 3, 2021): 10727. http://dx.doi.org/10.3390/ijms221910727.
Full textAbstract:
All eukaryotic cells are composed of the cytoskeleton, which plays crucial roles in coordinating diverse cellular functions such as cell division, morphology, migration, macromolecular stabilization, and protein trafficking. The cytoskeleton consists of microtubules, intermediate filaments, and actin filaments. Cofilin, an actin-depolymerizing protein, is indispensable for regulating actin dynamics in the central nervous system (CNS) development and function. Cofilin activities are spatiotemporally orchestrated by numerous extra- and intra-cellular factors. Phosphorylation at Ser-3 by kinases attenuate cofilin’s actin-binding activity. In contrast, dephosphorylation at Ser-3 enhances cofilin-induced actin depolymerization. Cofilin functions are also modulated by various binding partners or reactive oxygen species. Although the mechanism of cofilin-mediated actin dynamics has been known for decades, recent research works are unveiling the profound impacts of cofilin dysregulation in neurodegenerative pathophysiology. For instance, oxidative stress-induced increase in cofilin dephosphorylation is linked to the accumulation of tau tangles and amyloid-beta plaques in Alzheimer’s disease. In Parkinson’s disease, cofilin activation by silencing its upstream kinases increases α-synuclein-fibril entry into the cell. This review describes the molecular mechanism of cofilin-mediated actin dynamics and provides an overview of cofilin’s importance in CNS physiology and pathophysiology.
17
Kim, Dong Kyu, Dohyun Han, Joonho Park, Hyunjung Choi, Jong-Chan Park, Moon-Yong Cha, Jongmin Woo, et al. "Deep proteome profiling of the hippocampus in the 5XFAD mouse model reveals biological process alterations and a novel biomarker of Alzheimer’s disease." Experimental & Molecular Medicine 51, no. 11 (November 2019): 1–17. http://dx.doi.org/10.1038/s12276-019-0326-z.
Full textAbstract:
AbstractAlzheimer’s disease (AD), which is the most common type of dementia, is characterized by the deposition of extracellular amyloid plaques. To understand the pathophysiology of the AD brain, the assessment of global proteomic dynamics is required. Since the hippocampus is a major region affected in the AD brain, we performed hippocampal analysis and identified proteins that are differentially expressed between wild-type and 5XFAD model mice via LC-MS methods. To reveal the relationship between proteomic changes and the progression of amyloid plaque deposition in the hippocampus, we analyzed the hippocampal proteome at two ages (5 and 10 months). We identified 9,313 total proteins and 1411 differentially expressed proteins (DEPs) in 5- and 10-month-old wild-type and 5XFAD mice. We designated a group of proteins showing the same pattern of changes as amyloid beta (Aβ) as the Aβ-responsive proteome. In addition, we examined potential biomarkers by investigating secretory proteins from the Aβ-responsive proteome. Consequently, we identified vitamin K-dependent protein S (PROS1) as a novel microglia-derived biomarker candidate in the hippocampus of 5XFAD mice. Moreover, we confirmed that the PROS1 level in the serum of 5XFAD mice increases as the disease progresses. An increase in PROS1 is also observed in the sera of AD patients and shows a close correlation with AD neuroimaging markers in humans. Therefore, our quantitative proteome data obtained from 5XFAD model mice successfully predicted AD-related biological alterations and suggested a novel protein biomarker for AD.
18
Das, Rajib, Abdur Rauf, Saima Akhter, Mohammad Nazmul Islam, Talha Bin Emran, Saikat Mitra, Ishaq N. Khan, and Mohammad S. Mubarak. "Role of Withaferin A and Its Derivatives in the Management of Alzheimer’s Disease: Recent Trends and Future Perspectives." Molecules 26, no. 12 (June 17, 2021): 3696. http://dx.doi.org/10.3390/molecules26123696.
Full textAbstract:
Globally, Alzheimer’s disease (AD) is one of the most prevalent age-related neurodegenerative disorders associated with cognitive decline and memory deficits due to beta-amyloid deposition (Aβ) and tau protein hyperphosphorylation. To date, approximately 47 million people worldwide have AD. This figure will rise to an estimated 75.6 million by 2030 and 135.5 million by 2050. According to the literature, the efficacy of conventional medications for AD is statistically substantial, but clinical relevance is restricted to disease slowing rather than reversal. Withaferin A (WA) is a steroidal lactone glycowithanolides, a secondary metabolite with comprehensive biological effects. Biosynthetically, it is derived from Withania somnifera (Ashwagandha) and Acnistus breviflorus (Gallinero) through the mevalonate and non-mevalonate pathways. Mounting evidence shows that WA possesses inhibitory activities against developing a pathological marker of Alzheimer’s diseases. Several cellular and animal models’ particulates to AD have been conducted to assess the underlying protective effect of WA. In AD, the neuroprotective potential of WA is mediated by reduction of beta-amyloid plaque aggregation, tau protein accumulation, regulation of heat shock proteins, and inhibition of oxidative and inflammatory constituents. Despite the various preclinical studies on WA’s therapeutic potentiality, less is known regarding its definite efficacy in humans for AD. Accordingly, the present study focuses on the biosynthesis of WA, the epidemiology and pathophysiology of AD, and finally the therapeutic potential of WA for the treatment and prevention of AD, highlighting the research and augmentation of new therapeutic approaches. Further clinical trials are necessary for evaluating the safety profile and confirming WA’s neuroprotective potency against AD.
19
Angelova, Hristina Tz, Daniela M. Pechlivanova, Boycho V. Landzhov, and Elena B. Dzhambazova. "The Neuropeptide Kyotorphin as a Possible Biomarker and Neuroprotective Agent in Alzheimer’s Disease." Journal of Biomedical and Clinical Research 13, no. 1 (September 1, 2020): 8–18. http://dx.doi.org/10.2478/jbcr-2020-0002.
Full textAbstract:
Summary Alzheimer’s disease (AD) is an age-related neurodegenerative disorder clinically characterized by memory impairment, disorientation, cognitive deficits, and behavioral disturbances. The neuropathological features are amyloid plaques containing aggregated amyloid-beta (Aβ) peptide, neurofibrillary tangles composed of the hyperphosphorylated form of the microtubule protein tau (HP-tau), and loss of neurons and synapses in the brain. There are no effective strategies for the prevention or treatment of the disease, leading to an increased need for AD biomarkers to improve early detection, accurate diagnosis, and accelerate drug development in this field. Recently, increasing attention has been dedicated to neuropeptides in searching for new drug targets in the treatment of nervous system disorders. Available data suggest that many neuropeptides may be associated with the pathophysiology and potential therapy of AD because of their wide distribution in brain areas responsible for learning and memory processes and their predominately neuroprotective actions. This short review aimed to briefly describe the neuropathology of AD and summarize the data related to one of its recently proposed biomarker - kyotorphin (KTP) neuropeptide. Our previous experiments showed moderate and selective protective effects of KTP against the late consequences of the intracerebroventricular streptozotocin-induced AD model.
20
Scremin, Elena, Mario Agostini, Alessandro Leparulo, Tullio Pozzan, Elisa Greotti, and Cristina Fasolato. "ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells." International Journal of Molecular Sciences 21, no. 15 (July 25, 2020): 5288. http://dx.doi.org/10.3390/ijms21155288.
Full textAbstract:
Senile plaques, the hallmarks of Alzheimer’s Disease (AD), are generated by the deposition of amyloid-beta (Aβ), the proteolytic product of amyloid precursor protein (APP), by β and γ-secretase. A large body of evidence points towards a role for Ca2+ imbalances in the pathophysiology of both sporadic and familial forms of AD (FAD). A reduction in store-operated Ca2+ entry (SOCE) is shared by numerous FAD-linked mutations, and SOCE is involved in Aβ accumulation in different model cells. In neurons, both the role and components of SOCE remain quite obscure, whereas in astrocytes, SOCE controls their Ca2+-based excitability and communication to neurons. Glial cells are also directly involved in Aβ production and clearance. Here, we focus on the role of ORAI2, a key SOCE component, in modulating SOCE in the human neuroglioma cell line H4. We show that ORAI2 overexpression reduces both SOCE level and stores Ca2+ content, while ORAI2 downregulation significantly increases SOCE amplitude without affecting store Ca2+ handling. In Aβ-secreting H4-APPswe cells, SOCE inhibition by BTP2 and SOCE augmentation by ORAI2 downregulation respectively increases and decreases Aβ42 accumulation. Based on these findings, we suggest ORAI2 downregulation as a potential tool to rescue defective SOCE in AD, while preventing plaque formation.
21
Volmar, Claude-Henry, Hasib Salah-Uddin, Karolina J. Janczura, Paul Halley, Guerline Lambert, Andrew Wodrich, Sivan Manoah, et al. "M344 promotes nonamyloidogenic amyloid precursor protein processing while normalizing Alzheimer’s disease genes and improving memory." Proceedings of the National Academy of Sciences 114, no. 43 (October 9, 2017): E9135—E9144. http://dx.doi.org/10.1073/pnas.1707544114.
Full textAbstract:
Alzheimer’s disease (AD) comprises multifactorial ailments for which current therapeutic strategies remain insufficient to broadly address the underlying pathophysiology. Epigenetic gene regulation relies upon multifactorial processes that regulate multiple gene and protein pathways, including those involved in AD. We therefore took an epigenetic approach where a single drug would simultaneously affect the expression of a number of defined AD-related targets. We show that the small-molecule histone deacetylase inhibitor M344 reduces beta-amyloid (Aβ), reduces tau Ser396 phosphorylation, and decreases both β-secretase (BACE) and APOEε4 gene expression. M344 increases the expression of AD-relevant genes: BDNF, α-secretase (ADAM10), MINT2, FE65, REST, SIRT1, BIN1, and ABCA7, among others. M344 increases sAPPα and CTFα APP metabolite production, both cleavage products of ADAM10, concordant with increased ADAM10 gene expression. M344 also increases levels of immature APP, supporting an effect on APP trafficking, concurrent with the observed increase in MINT2 and FE65, both shown to increase immature APP in the early secretory pathway. Chronic i.p. treatment of the triple transgenic (APPsw/PS1M146V/TauP301L) mice with M344, at doses as low as 3 mg/kg, significantly prevented cognitive decline evaluated by Y-maze spontaneous alternation, novel object recognition, and Barnes maze spatial memory tests. M344 displays short brain exposure, indicating that brief pulses of daily drug treatment may be sufficient for long-term efficacy. Together, these data show that M344 normalizes several disparate pathogenic pathways related to AD. M344 therefore serves as an example of how a multitargeting compound could be used to address the polygenic nature of multifactorial diseases.
22
Kim, Min Woo, Kyonghwan Choe, Jun Sung Park, Hyeon Jin Lee, Min Hwa Kang, Riaz Ahmad, and Myeong Ok Kim. "Pharmacological Inhibition of Spleen Tyrosine Kinase Suppressed Neuroinflammation and Cognitive Dysfunction in LPS-Induced Neurodegeneration Model." Cells 11, no. 11 (May 28, 2022): 1777. http://dx.doi.org/10.3390/cells11111777.
Full textAbstract:
Tyrosine-protein kinase (Syk) plays a potential role in neuroinflammation and adaptive immune responses in several neurodegenerative conditions. Seeing the significant role of Syk in the pathophysiology of neurodegeneration, several pharmacological inhibitors have been developed. One of the known inhibitors of Syk is BAY61-3606, which has shown efficacies in Alzheimer’s disease (AD) through regulating amyloid production. However, little is known about its efficacies in neuroinflammation and neurodegeneration. Our finding showed that Syk expression was up-regulated by lipopolysaccharide (LPS)-dependent manner, and BAY61-3606 significantly suppressed the activated microglia (ionized calcium-binding adaptor molecule 1 [Iba-1]) and the inflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin 1-beta [IL-1β], IL-6) and other inflammatory mediators (nuclear factor kappa B [NF-κB], cyclooxygenase-2 [Cox-2], and inducible nitric axide synthase [iNOS]) in the lipopolysaccharide (LPS)-treated in vivo and in vitro models. Moreover, BAY61-3606 significantly reduced microglia-mediated neuronal cell death by regulating the expression of Cytochrome C and Bim (B-cell lymphoma 2 [BCL-2] interacting mediator of cell death) in the LPS-treated mice brain and HT22 cells. Furthermore, the expression of synaptic markers, synaptosomal-associated protein, 25 kDa (SNAP25), synaptophysin (Syp), and postsynaptic density protein-95 (PSD95) in LPS-challenged mice showed that BAY61-3606 significantly recovered the synaptic markers. Finally, we have analyzed the effects of BAY61-3606 against memory and cognitive dysfunctions in the LPS injected mice. The Y-maze test and Passive avoidance test suggested that BAY61-3606 significantly protected against LPS-induced cognitive and memory dysfunctions. The current findings not only highlight the mechanisms of Syk in the pathophysiology of neuro-inflammation, but also support the therapeutic efficacy of BAY61-3606 in the management of neurodegeneration.
23
Romaus-Sanjurjo, Daniel, Uxía Regueiro, Maite López-López, Laura Vázquez-Vázquez, Alberto Ouro, Isabel Lema, and Tomás Sobrino. "Alzheimer’s Disease Seen through the Eye: Ocular Alterations and Neurodegeneration." International Journal of Molecular Sciences 23, no. 5 (February 24, 2022): 2486. http://dx.doi.org/10.3390/ijms23052486.
Full textAbstract:
Alzheimer’s Disease (AD) is one of the main neurodegenerative diseases worldwide. Unfortunately, AD shares many similarities with other dementias at early stages, which impedes an accurate premortem diagnosis. Therefore, it is urgent to find biomarkers to allow for early diagnosis of the disease. There is increasing scientific evidence highlighting the similarities between the eye and other structures of the CNS, suggesting that knowledge acquired in eye research could be useful for research and diagnosis of AD. For example, the retina and optic nerve are considered part of the central nervous system, and their damage can result in retrograde and anterograde axon degeneration, as well as abnormal protein aggregation. In the anterior eye segment, the aqueous humor and tear film may be comparable to the cerebrospinal fluid. Both fluids are enriched with molecules that can be potential neurodegenerative biomarkers. Indeed, the pathophysiology of AD, characterized by cerebral deposits of amyloid-beta (Aβ) and tau protein, is also present in the eyes of AD patients, besides numerous structural and functional changes observed in the structure of the eyes. Therefore, all this evidence suggests that ocular changes have the potential to be used as either predictive values for AD assessment or as diagnostic tools.
24
Montanari, Serena, Marco Allarà, Laura Scalvini, Magdalena Kostrzewa, Federica Belluti, Silvia Gobbi, Marina Naldi, et al. "New Coumarin Derivatives as Cholinergic and Cannabinoid System Modulators." Molecules 26, no. 11 (May 28, 2021): 3254. http://dx.doi.org/10.3390/molecules26113254.
Full textAbstract:
In the last years, the connection between the endocannabinoid system (eCS) and neuroprotection has been discovered, and evidence indicates that eCS signaling is involved in the regulation of cognitive processes and in the pathophysiology of Alzheimer’s disease (AD). Accordingly, pharmacotherapy targeting eCS could represent a valuable contribution in fighting a multifaceted disease such as AD, opening a new perspective for the development of active agents with multitarget potential. In this paper, a series of coumarin-based carbamic and amide derivatives were designed and synthesized as multipotent compounds acting on cholinergic system and eCS-related targets. Indeed, they were tested with appropriate enzymatic assays on acetyl and butyryl-cholinesterases and on fatty acid amide hydrolase (FAAH), and also evaluated as cannabinoid receptor (CB1 and CB2) ligands. Moreover, their ability to reduce the self-aggregation of beta amyloid protein (Aβ42) was assessed. Compounds 2 and 3, bearing a carbamate function, emerged as promising inhibitors of hAChE, hBuChE, FAAH and Aβ42 self-aggregation, albeit with moderate potencies, while the amide 6 also appears a promising CB1/CB2 receptors ligand. These data prove for the new compounds an encouraging multitarget profile, deserving further evaluation.
25
Lampinen, Riikka, Mohammad Feroze Fazaludeen, Simone Avesani, Tiit Örd, Elina Penttilä, Juha-Matti Lehtola, Toni Saari, et al. "Single-Cell RNA-Seq Analysis of Olfactory Mucosal Cells of Alzheimer’s Disease Patients." Cells 11, no. 4 (February 15, 2022): 676. http://dx.doi.org/10.3390/cells11040676.
Full textAbstract:
Olfaction is orchestrated by olfactory mucosal cells located in the upper nasal cavity. Olfactory dysfunction manifests early in several neurodegenerative disorders including Alzheimer’s disease, however, disease-related alterations to the olfactory mucosal cells remain poorly described. The aim of this study was to evaluate the olfactory mucosa differences between cognitively healthy individuals and Alzheimer’s disease patients. We report increased amyloid-beta secretion in Alzheimer’s disease olfactory mucosal cells and detail cell-type-specific gene expression patterns, unveiling 240 differentially expressed disease-associated genes compared to the cognitively healthy controls, and five distinct cell populations. Overall, alterations of RNA and protein metabolism, inflammatory processes, and signal transduction were observed in multiple cell populations, suggesting their role in Alzheimer’s disease-related olfactory mucosa pathophysiology. Furthermore, the single-cell RNA-sequencing proposed alterations in gene expression of mitochondrially located genes in AD OM cells, which were verified by functional assays, demonstrating altered mitochondrial respiration and a reduction of ATP production. Our results reveal disease-related changes of olfactory mucosal cells in Alzheimer’s disease and demonstrate the utility of single-cell RNA sequencing data for investigating molecular and cellular mechanisms associated with the disease.
26
de la Torre, Jack C. "Cardiovascular Risk Factors Promote Brain Hypoperfusion Leading to Cognitive Decline and Dementia." Cardiovascular Psychiatry and Neurology 2012 (December 3, 2012): 1–15. http://dx.doi.org/10.1155/2012/367516.
Full textAbstract:
Heart disease is the major leading cause of death and disability in the world. Mainly affecting the elderly population, heart disease and its main outcome, cardiovascular disease, have become an important risk factor in the development of cognitive decline and Alzheimer’s disease (AD). This paper examines the evidence linking chronic brain hypoperfusion induced by a variety of cardiovascular deficits in the development of cognitive impairment preceding AD. The evidence indicates a strong association between AD and cardiovascular risk factors, including ApoE4, atrial fibrillation, thrombotic events, hypertension, hypotension, heart failure, high serum markers of inflammation, coronary artery disease, low cardiac index, and valvular pathology. In elderly people whose cerebral perfusion is already diminished by their advanced age, additional reduction of cerebral blood flow stemming from abnormalities in the heart-brain vascular loop ostensibly increases the probability of developing AD. Evidence also suggests that a neuronal energy crisis brought on by relentless brain hypoperfusion may be responsible for protein synthesis abnormalities that later result in the classic neurodegenerative lesions involving the formation of amyloid-beta plaques and neurofibrillary tangles. Insight into how cardiovascular risk factors can induce progressive cognitive impairment offers an enhanced understanding of the multifactorial pathophysiology characterizing AD and ways at preventing or managing the cardiovascular precursors of this dementia.
27
Kim, Young-Kook, Yoon Seok Jung, and Juhyun Song. "Transcriptome Profile in the Mouse Brain of Hepatic Encephalopathy and Alzheimer’s Disease." International Journal of Molecular Sciences 24, no. 1 (December 30, 2022): 675. http://dx.doi.org/10.3390/ijms24010675.
Full textAbstract:
Hepatic encephalopathy (HE) is a chronic metabolic disease accompanied by neuropathological and neuropsychiatric features, including memory deficits, psychomotor dysfunction, depression, and anxiety. Alzheimer’s disease (AD), the most common neurodegenerative disease, is characterized by tau hyperphosphorylation, excessive amyloid beta (Aβ) accumulation, the formation of fibrillary tangles, hippocampus atrophy, and neuroinflammation. Recent studies have suggested a positive correlation between HE and AD. Some studies reported that an impaired cholesterol pathway, abnormal bile acid secretion, excessive ammonia level, impaired Aβ clearance, astrocytic dysfunction, and abnormal γ-aminobutyric acid GABAergic neuronal signaling in HE may also be involved in AD pathology. However, the mechanisms and related genes involved in AD-like pathology in the HE brain are unclear. Thus, we compared the cortical transcriptome profile between an HE mouse model, bile duct ligation (BDL), and an AD mouse model, the 5×FAD. Our study showed that the expression of many genes implicated in HE is associated with neuronal dysfunction in AD mice. We found changes in various protein-coding RNAs, implicated in synapses, neurogenesis, neuron projection, neuron differentiation, and neurite outgrowth, and non-coding RNAs possibly associated with neuropathology. Our data provide an important resource for further studies to elucidate AD-like pathophysiology in HE patients.
28
Gong, Mengting, Shoudong Ye, Wen-Xing Li, Jian Zhang, Yanjun Liu, Jie Zhu, Wenwen Lv, et al. "Regulatory function of praja ring finger ubiquitin ligase 2 mediated by the P2rx3/P2rx7 axis in mouse hippocampal neuronal cells." American Journal of Physiology-Cell Physiology 318, no. 6 (June 1, 2020): C1123—C1135. http://dx.doi.org/10.1152/ajpcell.00070.2019.
Full textAbstract:
Praja2 ( Pja2), a member of the growing family of mammalian RING E3 ubiquitin ligases, is reportedly involved in not only several types of cancer but also neurological diseases and disorders, but the genetic mechanism underlying the regulation of Pja2 in the nervous system remains unclear. To study the cellular and molecular functions of Pja2 in mouse hippocampal neuronal cells (MHNCs), we used gain- and loss-of-function manipulations of Pja2 in HT-22 cells and tested their regulatory effects on three Alzheimer's disease (AD) genes and cell proliferation. The results revealed that the expression of AD markers, including amyloid beta precursor protein ( App), microtubule-associated protein tau ( Mapt), and gamma-secretase activating protein ( Gsap), could be inhibited by Pja2 overexpression and activated by Pja2 knockdown. In addition, HT-22 cell proliferation was enhanced by Pja2 upregulation and suppressed by its downregulation. We also evaluated and quantified the targets that responded to the enforced expression of Pja2 by RNA-Seq, and the results showed that purinergic receptor P2X, ligand-gated ion channel 3 and 7 ( P2rx3 and P2rx7), which show different expression patterns in the critical calcium signaling pathway, mediated the regulatory effect of Pja2 in HT-22 cells. Functional studies indicated that Pja2 regulated HT-22 cells development and AD marker genes by inhibiting P2rx3 but promoting P2rx7, a gene downstream of P2rx3. In conclusion, our results provide new insights into the regulatory function of the Pja2 gene in MHNCs and thus underscore the potential relevance of this molecule to the pathophysiology of AD.
29
Haque, Syed S. "Biomarkers in the diagnosis of neurodegenerative diseases." RUDN Journal of Medicine 26, no. 4 (December 23, 2022): 431–40. http://dx.doi.org/10.22363/2313-0245-2022-26-4-431-440.
Full textAbstract:
Biomarkers are molecules that behave as of biological states. Ideally, they should have high sensitivity, specificity, and accuracy in reflecting the total disease burden. The review discusses the current status of biomarkers used in neurological disorders. Neurodegenerative diseases are a heterogeneous group disorders characterized by progressive loss of structure and function of the central nervous system or peripheral nervous system. The review discusses the main biomarkers that have predictive value for describing clinical etiology, pathophysiology, and intervention strategies. Preciseness and reliability are one of important requirement for good biomarker. As a result of the analysis of literature data, it was revealed that beta-amyloid, total tau protein and its phosphorylated forms are the first biochemical biomarkers of neurodegenerative diseases measured in cerebrospinal fluid, but these markers are dependent upon invasive lumbar puncture and therefore it’s a cumbersome process for patients. Among the various biomarkers of neurodegenerative diseases, special attention is paid to miRNAs. MicroRNAs, important biomarkers in many disease states, including neurodegenerative disorders, make them promising candidates that may lead to identify new therapeutic targets. Conclusions. Biomarkers of neurological disease are present optimal amount in the cerebrospinal fluid but they are also present in blood at low levels. The data obtained reveal the predictive value of molecular diagnostics of neurodegenerative disorders and the need for its wider use.
30
Young, Malaney C., Nagamani Vunnam, Robyn T. Rebbeck, Samantha L. Yuen, David D. Thomas, and Jonathan N. Sachs. "Indirubin Inhibits TRAIL-Induced Activation of Death Receptor 5 in Jurkat Cells." Natural Product Communications 18, no. 1 (January 2023): 1934578X2211445. http://dx.doi.org/10.1177/1934578x221144580.
Full textAbstract:
Death receptor 5 (DR5) is an apoptosis-inducing membrane receptor that mediates cell death in several life-threatening conditions. There is a crucial need for the discovery of DR5 antagonists for the therapeutic intervention of conditions in which the overactivation of DR5 underlies the pathophysiology. DR5 activation mediates cell death in non-alcoholic fatty liver disease (NAFLD) and neurodegenerative processes including amyloid-beta (Aβ) accumulation, spinal cord injury (SCI), and brain ischemia. In the current work, we used fluorescence resonance energy transfer (FRET) to monitor the conformational dynamics of DR5 that mediate death signaling. We used a time-resolved FRET screening platform to screen the Selleck library of 2863 U.S. Food and Drug Administration (FDA)-approved compounds. The high-throughput screen (HTS) identified 13 compounds that modulated the FRET between DR5 monomers beyond 5 median absolute deviations (MADs) from the DMSO controls. Of these 13 compounds, indirubin was identified to specifically inhibit tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced caspase-8 activity without modulating DR5 surface expression or TRAIL binding. Indirubin inhibited Fas-associated death domain (FADD) oligomerization and increased cellular FLICE-inhibitory protein (c-FLIP) expression; both are molecular mechanisms involved in inhibiting the DR5 signaling cascade. This study has elucidated previously unknown properties of indirubin that make it a promising candidate for therapeutic investigation of diseases in which overactivation of DR5 underlies pathology.
31
Potenza, Maria Assunta, Luca Sgarra, Vanessa Desantis, Carmela Nacci, and Monica Montagnani. "Diabetes and Alzheimer’s Disease: Might Mitochondrial Dysfunction Help Deciphering the Common Path?" Antioxidants 10, no. 8 (August 6, 2021): 1257. http://dx.doi.org/10.3390/antiox10081257.
Full textAbstract:
A growing number of clinical and epidemiological studies support the hypothesis of a tight correlation between type 2 diabetes mellitus (T2DM) and the development risk of Alzheimer’s disease (AD). Indeed, the proposed definition of Alzheimer’s disease as type 3 diabetes (T3D) underlines the key role played by deranged insulin signaling to accumulation of aggregated amyloid beta (Aβ) peptides in the senile plaques of the brain. Metabolic disturbances such as hyperglycemia, peripheral hyperinsulinemia, dysregulated lipid metabolism, and chronic inflammation associated with T2DM are responsible for an inefficient transport of insulin to the brain, producing a neuronal insulin resistance that triggers an enhanced production and deposition of Aβ and concomitantly contributes to impairment in the micro-tubule-associated protein Tau, leading to neural degeneration and cognitive decline. Furthermore, the reduced antioxidant capacity observed in T2DM patients, together with the impairment of cerebral glucose metabolism and the decreased performance of mitochondrial activity, suggests the existence of a relationship between oxidative damage, mitochondrial impairment, and cognitive dysfunction that could further reinforce the common pathophysiology of T2DM and AD. In this review, we discuss the molecular mechanisms by which insulin-signaling dysregulation in T2DM can contribute to the pathogenesis and progression of AD, deepening the analysis of complex mechanisms involved in reactive oxygen species (ROS) production under oxidative stress and their possible influence in AD and T2DM. In addition, the role of current therapies as tools for prevention or treatment of damage induced by oxidative stress in T2DM and AD will be debated.
32
Ostrovska, S. S., V. F. Shatorna, and E. O. Liholetov. "Intracellular ways of development of Alzheimer's disease against the background of herpes viral infections (literature review)." Medicni perspektivi (Medical perspectives) 26, no. 1 (March 26, 2021): 40–46. http://dx.doi.org/10.26641/2307-0404.2021.1.227729.
Full textAbstract:
The concept of the viral etiology of Alzheimer's disease (AD) was first proposed in 1982. Its author MJ Ball suggested that the herpes simplex virus (HSV1) may be involved in the pathogenesis of AD, finding that the areas of the brain damaged in acute herpetic encephalitis are the same as those that are affected in AD, and those who survived usually suffer from memory loss and other cognitive impairment typical of AD. Subsequently, in all postmortem brain samples (temporal, frontal, and hippocampal) viral sequences of the viral thymidinekinase gene were found in a high proportion (70-100%) both in AD and in elderly people without it, while in young people and children the virus was found in very low proportions, so it was suggested that HSV1 comes from the peripheral ganglia, where the virus can remain inactive for many years, then enters the brain at an older age due to a decrease in the activity of the immune system. The increased risk of AD is associated with the presence of HSV1 in the brain and the carriage of a specific genetic factor – allele-ε4 of the apolipoprotein E4 gene (APOE-ε4). By themselves, neither HSV1 nor the APOE-ɛ4 allele were found as risk factors for the development of AD but their combination increased the risk of AD development by 12 times and made up 60% in patients with AD. The phenomena involved in the pathophysiology of AD are neurodegenerative changes that occur as a result of fibrillation and deposition of amyloid-β-peptide (Aβ) and neurofibrillary tangles – accumulations of aggregated phosphorylated tau-proteins (P-tau), leading to brain atrophy due to neuronal death. Traditionally, Aβ has been characterized as a catabolic by-product. However, it has recently been shown that Aβ-peptide has antiviral activity and protective effects against HSV infections in the brain. А 16-year study in Thailand with more than 33,000 patients showed that long-term use of antiherpetic drugs reduces the risk of dementia, including AD patients infected with HSV1. Patients with HSV1 infection who received antiherpetic drugs showed a lower risk of all types of dementia compared with the group without these drugs. Their positive effect on stopping the accumulation of amyloid beta and tau protein in the body has been confirmed. In this regard, it is assumed that vaccination against HSV1 may be useful not only for treatment, but also for the prevention of AD.
33
Vojdani, Aristo, and Elroy Vojdani. "Amyloid-Beta 1-42 Cross-Reactive Antibody Prevalent in Human Sera May Contribute to Intraneuronal Deposition of A-Beta-P-42." International Journal of Alzheimer's Disease 2018 (June 21, 2018): 1–12. http://dx.doi.org/10.1155/2018/1672568.
Full textAbstract:
Antibodies against many neural antigens are detected in the sera of both patients with Alzheimer’s disease (AD) and some healthy individuals. Blood-brain barrier dysfunction could make it possible for brain-reactive autoantibodies to reach the brain, where they can react with amyloid ß peptide (AßP). The origin of these autoreactive antibodies in the blood is unclear. The goals of this study were as follows: (1) to examine the immune reactivity of anti-AßP-42 with 22 neuronal and other associated antigens, some of which are involved in the pathophysiology of AD; (2) to classify antibodies to these 22 different antigens into those that cross-react with AßP-42 and those that do not; (3) to determine whether these antibodies react with BBB proteins, nerve growth factors, and enteric neuronal antigens. Using monoclonal AßP-42 antibody and ELISA methodology, we found that the antibody was highly reactive with Aß protein, tau protein, presenilin, rabaptin-5,β-NGF, BDNF, mTG, and enteric nerve. The same antibody produced equivocal to moderate reactions with glutamate-R, S100B, AQP4, GFAP, MBP,α-synuclein, tTG-2, and tTG-3, and not with the rest. These antibodies were also measured in blood samples from 47 AD patients and 47 controls. IgG antibodies were found to be elevated against AßP-42 and many other antigens in a significant percentage of controls. Overall, the mean OD values were significantly higher against 9/23 tested antigens (p<0.001) in the samples with AD. We were indeed able to classify the detected neuronal antibodies into those that cross-react with AßP-42 and those that do not. Our main finding is that although these antibodies may be harmless in a subgroup of controls, in individuals with compromised BBBs these antibodies that cross-react with AßP-42 can reach the brain, where their cross-reactivity with AßP-42 may contribute to the onset and progression of AD, and perhaps other neurodegenerative disorders.
34
O'Connor, Antoinette, Josef Pannee, Teresa Poole, Charles Arber, Erik Portelius, Imogen J. Swift, Amanda J. Heslegrave, et al. "Plasma amyloid-β ratios in autosomal dominant Alzheimer’s disease: the influence of genotype." Brain, April 23, 2021. http://dx.doi.org/10.1093/brain/awab166.
Full textAbstract:
Abstract In-vitro studies of autosomal dominant Alzheimer’s disease implicate longer amyloid-beta peptides in disease pathogenesis, however less is known about the behaviour of these mutations in-vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at-risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-beta42:38, 42:40 and 38:40 ratios between presenilin1 and amyloid precursor protein carriers. We examined the relationship between plasma and in-vitro models of amyloid-beta processing and tested for associations with parental age at onset. 39 participants were mutation carriers (28 presenilin1 and 11 amyloid precursor protein). Age- and sex-adjusted models showed marked differences in plasma amyloid-beta between genotypes: higher amyloid-beta42:38 in presenilin1 versus amyloid precursor protein (p < 0.001) and non-carriers (p < 0.001); higher amyloid-beta38:40 in amyloid precursor protein versus presenilin1 (p < 0.001) and non-carriers (p < 0.001); while amyloid-beta42:40 was higher in both mutation groups compared to non-carriers (both p < 0.001). Amyloid-beta profiles were reasonably consistent in plasma and cell lines. Within presenilin1, models demonstrated associations between amyloid-beta42:38, 42:40 and 38:40 ratios and parental age at onset. In-vivo differences in amyloid-beta processing between presenilin1 and amyloid precursor protein carriers provide insights into disease pathophysiology, which can inform therapy development.
35
Spotorno, Nicola, Chloé Najac, Erik Stomrud, Niklas Mattsson-Carlgren, Sebastian Palmqvist, Danielle van Westen, Itamar Ronen, and Oskar Hansson. "Astrocytic function is associated with both amyloid-β and tau pathology in non-demented APOE ε4 carriers." Brain Communications, May 22, 2022. http://dx.doi.org/10.1093/braincomms/fcac135.
Full textAbstract:
Abstract A growing body of evidence suggests that astrocytes play a major role in the pathophysiology of Alzheimer’s disease. Given that APOE is primarily expressed in astrocytes, these cells might be an important link between the APOE ε4 allele and development of Alzheimer’s disease pathology. Here, we investigate this hypothesis in vivo by measuring myo-Inositol, a metabolite involved in astrocytic functions, with magnetic resonance spectroscopy. Currently, there are conflicting evidence regarding the relationship between APOE ε4 and myo-Inositol concentration. Furthermore, data supporting a relationship between APOE ε4, myo-Inositol and Alzheimer’s disease pathology (amyloid-beta and tau proteins) in the preclinical stage of Alzheimer’s disease are limited. A previous study revealed differences in myo-Inositol levels between APOE ε4 carriers and noncarriers already in preclinical Alzheimer’s disease participant. However, other reports showed no impact of APOE genotype on the association between myo-Inositol and rate of amyloid-beta accumulation. In the present study we determined the effect of APOE genotype on the association between myo-Inositol and both amyloid-β and tau deposition quantified by PET in 428 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER-2 cohort. APOE genotype impacted the associations between myo-Inositol and amyloid-β pathology as revealed by an interaction effect between APOE genotype and levels of myo-inositol (p < 0.001) such that higher myo-Inositol concentration was related to more amyloid-beta pathology in APOE ε4 carriers only. A similar interaction effect was also found when investigating the effect of APOE on the association between myo-inositol and tau pathology (p < 0.01). Focusing on the APOE ε4 subsample, myo-Inositol partially (17%) mediated the association between amyloid-beta and tau pathology (p < 0.05). Further, in a subgroup of participants with available plasma levels of glial fibrillary acidic protein, a marker of astroglial activation and astrocytosis, we found that glial fibrillary acidic protein correlated with myo-inositol only in APOE e4 carriers (APOE ε4 carriers: p < 0.01; APOE ε4 non carriers: p > 0.8), suggesting that myo-Inosotol might reflect an aspect of the astrocytic involvement in Alzheimer’s pathology which is specific to the impact of APOE ε4. Therefore, we suggest that myo-Inositol is a candidate in vivo marker to study the impact of APOE ε4 on the interplay between astrocytes and the pathophysiology of Alzheimer’s disease.
36
Morris, J. C. "EDITORIAL: IS NOW THE TIME FOR COMBINATION THERAPIES FOR ALZHEIMER DISEASE?" Journal Of Prevention of Alzheimer's Disease, 2019, 1–2. http://dx.doi.org/10.14283/jpad.2019.15.
Full textAbstract:
In this issue, Gauthier and colleagues from the European Union-North America Clinical Trials in Alzheimer Disease Task Force (EU/US CTAD Task Force) provide a compelling argument for the implementation of clinical trials in persons with Alzheimer disease (AD) dementia that utilize combinations of experimental anti-Alzheimer therapies (1). The rationale for combination therapy in AD rests on the appreciation that AD pathophysiology is complex and involves many pathogenic pathways (2). The EU/US CTAD Task Force recommends that combination therapies should include therapies that target various aspects of the process wherein amyloid precursor protein undergoes proteolytic cleavage to produce amyloidogenic peptides. That anti-amyloid monotherapy alone is insufficient to provide clinical benefit with AD dementia has been underscored once again by the recent decision of Biogen and Eisai to discontinue Phase 3 studies of aducanumab, a human monoclonal antibody that targets aggregated forms of amyloid-beta, because futility analyses indicated that the trials were unlikely to meet their primary endpoint (3); similarly, Roche has announced discontinuation of trials of crenezumab (4). The EU/US CTAD Task Force nonetheless recommends that therapies that target amyloid-beta should be considered for inclusion in combination clinical trials in AD dementia, given the preponderance of evidence that disruptions in amyloid-beta production, clearance, or processing are very likely to be involved with, or even initiate, AD pathogenesis (5).
37
Jennings, Matthew J., Denisa Hathazi, Chi D. L. Nguyen, Benjamin Munro, Ute Münchberg, Robert Ahrends, Annette Schenck, et al. "Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3." Frontiers in Cell and Developmental Biology 9 (October 6, 2021). http://dx.doi.org/10.3389/fcell.2021.710247.
Full textAbstract:
Recessive mutations in DNAJC3, an endoplasmic reticulum (ER)-resident BiP co-chaperone, have been identified in patients with multisystemic neurodegeneration and diabetes mellitus. To further unravel these pathomechanisms, we employed a non-biased proteomic approach and identified dysregulation of several key cellular pathways, suggesting a pathophysiological interplay of perturbed lipid metabolism, mitochondrial bioenergetics, ER-Golgi function, and amyloid-beta processing. Further functional investigations in fibroblasts of patients with DNAJC3 mutations detected cellular accumulation of lipids and an increased sensitivity to cholesterol stress, which led to activation of the unfolded protein response (UPR), alterations of the ER-Golgi machinery, and a defect of amyloid precursor protein. In line with the results of previous studies, we describe here alterations in mitochondrial morphology and function, as a major contributor to the DNAJC3 pathophysiology. Hence, we propose that the loss of DNAJC3 affects lipid/cholesterol homeostasis, leading to UPR activation, β-amyloid accumulation, and impairment of mitochondrial oxidative phosphorylation.
38
Lee, Ellen E., Charisse Winston-Gray, James W. Barlow, Robert A. Rissman, and Dilip V. Jeste. "Plasma Levels of Neuron- and Astrocyte-Derived Exosomal Amyloid Beta1-42, Amyloid Beta1-40, and Phosphorylated Tau Levels in Schizophrenia Patients and Non-psychiatric Comparison Subjects: Relationships With Cognitive Functioning and Psychopathology." Frontiers in Psychiatry 11 (March 2, 2021). http://dx.doi.org/10.3389/fpsyt.2020.532624.
Full textAbstract:
Introduction: Cognitive deficits in people with schizophrenia (PWS) are a major predictor of disability and functioning, yet the underlying pathophysiology remains unclear. A possible role of amyloid and tau biomarkers (hallmarks of Alzheimer's disease) is still speculative in schizophrenia. Exosomes or extracellular vesicles, involved with cell-to-cell communication and waste removal, can be used to assay brain-based proteins from peripheral blood. To our knowledge, this is the first study of exosomal amyloid and tau protein levels in PWS.Methods: This cross-sectional study included 60 PWS and 60 age- and sex-comparable non-psychiatric comparison subjects (NCs), age range 26–65 years. Assessments of global cognitive screening, executive functioning, psychopathology, and physical measures were conducted. Exosomes were extracted and precipitated from fasting plasma and identified as neuron-derived exosomes (NDEs) or astrocyte-derived exosomes (ADEs). Human-specific ELISAs were used to assay levels of amyloid-beta 1-42 (Aβ42), amyloid-beta 1-40 (Aβ40), and phosphorylated T181 tau (P-T181-tau). Plasma assays for aging biomarkers (C-reactive protein and F2-isoprostanes) were also performed.Results: ADE-Aβ42 levels were higher in PWS compared to NCs, though the other exosomal markers were similar between the two groups. Higher ADE-P-T181-tau levels were associated with worse executive functioning. Among PWS, higher ADE-P-T181-tau levels were associated with less severe negative symptoms and increased F2-isoprostane levels. Astrocyte-derived Aβ marker levels were sensitive and specific in differentiating between diagnostic groups. Among PWS, Aβ40 levels differed most by exosomal origin.Discussion: Exosomal markers may provide novel insights into brain-based processes (e.g., aging, oxidative stress) from peripheral blood samples.
39
Yao, Weiwei, Huihui Yang, and Jinfei Yang. "Small-molecule drugs development for Alzheimer's disease." Frontiers in Aging Neuroscience 14 (November 1, 2022). http://dx.doi.org/10.3389/fnagi.2022.1019412.
Full textAbstract:
Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no effective therapeutic drugs currently. The complicated pathophysiology of AD is not well understood, although beta-amyloid (Aβ) cascade and hyperphosphorylated tau protein were regarded as the two main causes of AD. Other mechanisms, such as oxidative stress, deficiency of central cholinergic neurotransmitters, mitochondrial dysfunction, and inflammation, were also proposed and studied as targets in AD. This review aims to summarize the small-molecule drugs that were developed based on the pathogenesis and gives a deeper understanding of the AD. We hope that it could help scientists find new and better treatments to gradually conquer the problems related to AD in future.
40
Remnestål, Julia, Sofia Bergström, Jennie Olofsson, Evelina Sjöstedt, Mathias Uhlén, Kaj Blennow, Henrik Zetterberg, et al. "Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds." Alzheimer's Research & Therapy 13, no. 1 (March 2, 2021). http://dx.doi.org/10.1186/s13195-021-00789-5.
Full textAbstract:
Abstract Background Increased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer’s disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognized, the need for further characterization of the pathophysiological mechanisms behind AD still remains. Methods In this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology. Results The protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score. Conclusions We identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins’ role in AD pathophysiology.
41
Ibanez, Laura, Jorge A. Bahena, Chengran Yang, Umber Dube, Fabiana H. G. Farias, John P. Budde, Kristy Bergmann, et al. "Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease." Acta Neuropathologica Communications 8, no. 1 (November 19, 2020). http://dx.doi.org/10.1186/s40478-020-01072-8.
Full textAbstract:
AbstractAlpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson’s disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta1–42, total tau, and phosphorylated tau181 as quantitative traits in genetic studies have provided novel insights into Alzheimer’s disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson’s disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson’s disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta1–42 levels (effect = − 0.5, p = 9.2 × 10−19). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau181 levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson’s disease risk meta-analysis were associated with Parkinson’s disease status (p = 0.035) and the genomic architecture of CSF amyloid beta1–42 (R2 = 2.29%; p = 2.5 × 10−11). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta1–42 levels (p = 7.3 × 10−04). Two-sample Mendelian Randomization revealed that CSF amyloid beta1–42 plays a role in Parkinson’s disease (p = 1.4 × 10−05) and age at onset (p = 7.6 × 10−06), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta1–42 (p = 3.8 × 10−06), higher mean cortical binding potentials (p = 5.8 × 10−08), and higher Braak amyloid beta score (p = 4.4 × 10−04). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson’s disease, CSF amyloid beta1–42, and APOE.
42
Artola Arita, V. A., B. T. Santeman, I. E. Sama, M. Kloosterman, I. Van Gelder, P. Van Der Meer, C. C. Lang, D. J. Van Veldhuisen, A. A. Voors, and M. Rienstra. "P566Activated amyloid-beta pathways in patients with atrial fibrillation and heart failure, a pathway analysis in BIOSTAT." EP Europace 22, Supplement_1 (June 1, 2020). http://dx.doi.org/10.1093/europace/euaa162.235.
Full textAbstract:
Abstract Funding Acknowledgements European Commission [FP7-242209-BIOSTAT-CHF], European Union’s Horizon 2020 under the Marie Skłodowska-Curie grant agreement No 754425 Background. Atrial fibrillation (AF) and heart failure (HF) are two growing epidemics that frequently co-exist, share clinical risk factors, and predispose to each other. There is limited understanding of the underlying pathophysiology of the combination of both conditions. Purpose. To perform pathway analyses of circulating plasma proteins and evaluate whether patients with both HF and AF have different activated pathways compared to those with HF without AF. Methods. We performed pathway overrepresentation analyses of differentially expressed plasma proteins in HF, with reduced (HFrEF) and preserved (HFpEF) ejection fraction, with AF versus sinus rhythm on ECG at enrolment in BIOSTAT-CHF, using 92 cardiovascular biomarkers. Pathway analyses were performed based on existing knowledge using Gene Ontology, REACTOME, and KEGG, to study underlying activated biological pathways. Resulting pathways were corrected by Bonferroni method. Results. We studied 2,839 patients with HF irrespective of their ejection fraction of whom 1,116 (39%) had AF and 1,723 (61%) were in sinus rhythm. HF patients with AF were older (76 ± 10 vs. 70 ± 12, p < 0.001), were less women (28% vs. 34%, p < 0.001), had history of stroke (16% vs. 10%, p < 0.001), renal disease (39% vs. 31%, p < 0.001) and less history of coronary artery disease (40% vs. 53%, p < 0.001). There were no significant differences in patients with hypertension (62% vs. 60 %, p = 0.22), diabetes (32% vs. 31%, p = 0.51) and COPD (18% vs. 16%, p = 0.20). A total of 1,661 (59%) had HFrEF and 432 (15%) had HFpEF. Pathway overrepresentation analyses revealed three amyloid-related pathways statically significant in total HF group, and in HFrEF and HFpEF respectively, with AF compared with those in sinus rhythm: amyloid-beta formation (p < 4.0E-4, p < 7.4E-6), amyloid-beta metabolic process (p < 1.0E-3, p < 1.9E-5), and amyloid precursor protein catabolic process (p < 9.1E-4, p < 1.6E-5). The key proteins related to these processes were spondin-1 (SPON-1), insulin-like growth factor binding protein 1 (IGFBP-1) and 7 (IGFBP-7). After adjusting for sex and age and correcting for multiple testing with fall discovery rate (FDR), SPON-1 (FDR < 6.3E-6), IGFBP-1 (FDR < 6.6E-3) and IGFBP-7 (FDR < 2.5E-9) remained statically significant in HFrEF patients with AF vs. sinus rhythm; whereas only SPON-1 (FDR < 7.3 E-3) and IGFBP-7 (FDR < 1.9E-3) remained in HFpEF patients with AF vs. sinus rhythm. Conclusion. Pathway analyses revealed activation of amyloid-beta pathways in HF patients with AF versus sinus rhythm with SPON-1, IGFBP-1 and IGFBP-7 overrepresented proteins. Amyloid-beta pathways may play a role in the pathophysiology of the combination of HF and AF, which needs to be replicated and validated in additional cohorts. Figure. Pathway analysis of activated proteins in patients with HF, HFrEF (A) and HFpEF (B) and AF versus sinus rhythm. Proteins are represented as dots and pathways as circumferences. Abstract Figure. Pathway overrepresentation analysis
43
Flores, Joseph, Anastasia Noël, Bénédicte Foveau, Olivier Beauchet, and Andréa C. LeBlanc. "Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging." Nature Communications 11, no. 1 (September 11, 2020). http://dx.doi.org/10.1038/s41467-020-18405-9.
Full textAbstract:
Abstract Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APPSw/Ind) J20 and wild-type mice with VX-765 delays both APPSw/Ind- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aβ) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.
44
Tomaszewski, S., S. Gauthier, A. Wimo, and P. Rosa-Neto. "COMBINATION THERAPY OF ANTI-TAU AND ANTI-AMYLOID DRUGS FOR DISEASE MODIFICATION IN EARLY-STAGE ALZHEIMER’S DISEASE: SOCIO-ECONOMIC CONSIDERATIONS MODELED ON TREATMENTS FOR TUBERCULOSIS, HIV/AIDS AND BREAST CANCER." Journal of Prevention of Alzheimer's Disease, 2015, 1–9. http://dx.doi.org/10.14283/jpad.2015.85.
Full textAbstract:
Current drugs for treatment of mild to severe dementia of the Alzheimer’s type include cholinesterase inhibitors and the NMDA non-competitive receptor antagonist memantine. There is controversy as to the additive benefit of these symptomatic drugs, and their effects are clinically modest. Patients with Alzheimer’s disease (AD) are known to have characteristic pathology, including senile plaques with amyloid beta-protein aggregates and neurofibrillary tangles with assembled tau proteins, which start in the hippocampus and spread to neighboring areas. Amyloid and tau modifying drugs are under clinical testing. Based on this pathophysiology, it is crucial to investigate whether anti-amyloid and anti-tau combined therapy would show efficacy in early stage of AD, beyond what could be achieved with anti-amyloid or anti-tau monotherapy. It is equally important to consider the socio-economic implications of such a combination therapy, if effective. We hypothesize that the high costs of combination therapy for early-stage AD patients will require societal and public health initiatives to ensure universal access to AD treatment. In order to better predict these socio-economic implications, we summarize the management of other combination therapies used for tuberculosis, HIV/AIDS, and breast cancer, based on a database search of PubMed and other relevant sources. We put forward a framework for testing a potential anti-amyloid and anti-tau disease modifying combination therapy for early-stage AD patients and present an analysis of the socio-economic implications of such a combination therapy.
45
Tobieson, Lovisa, Henrik Zetterberg, Kaj Blennow, and Niklas Marklund. "Extracellular fluid, cerebrospinal fluid and plasma biomarkers of axonal and neuronal injury following intracerebral hemorrhage." Scientific Reports 11, no. 1 (August 20, 2021). http://dx.doi.org/10.1038/s41598-021-96364-x.
Full textAbstract:
AbstractSpontaneous intracerebral hemorrhage (ICH) is the most devastating form of stroke. To refine treatments, improved understanding of the secondary injury processes is needed. We compared energy metabolic, amyloid and neuroaxonal injury biomarkers in extracellular fluid (ECF) from the perihemorrhagic zone (PHZ) and non-injured (NCX) brain tissue, cerebrospinal fluid (CSF) and plasma. Patients (n = 11; age 61 ± 10 years) undergoing ICH surgery received two microdialysis (MD) catheters, one in PHZ, and one in NCX. ECF was analysed at three time intervals within the first 60 h post- surgery, as were CSF and plasma samples. Amyloid-beta (Aβ) 40 and 42, microtubule associated protein tau (tau), and neurofilament-light (NF-L) were analysed using Single molecule array (Simoa) technology. Median biomarker concentrations were lowest in plasma, higher in ECF and highest in CSF. Biomarker levels varied over time, with different dynamics in the three fluid compartments. In the PHZ, ECF levels of Aβ40 were lower, and tau higher when compared to the NCX. Altered levels of Aβ peptides, NF-L and tau may reflect brain tissue injury following ICH surgery. However, the dynamics of biomarker levels in the different fluid compartments should be considered in the study of pathophysiology or biomarkers in ICH patients.
46
Cao, Lei, Yanyan Kong, Bin Ji, Yutong Ren, Yihui Guan, and Ruiqing Ni. "Positron Emission Tomography in Animal Models of Tauopathies." Frontiers in Aging Neuroscience 13 (January 10, 2022). http://dx.doi.org/10.3389/fnagi.2021.761913.
Full textAbstract:
The microtubule-associated protein tau (MAPT) plays an important role in Alzheimer’s disease and primary tauopathy diseases. The abnormal accumulation of tau contributes to the development of neurotoxicity, inflammation, neurodegeneration, and cognitive deficits in tauopathy diseases. Tau synergically interacts with amyloid-beta in Alzheimer’s disease leading to detrimental consequence. Thus, tau has been an important target for therapeutics development for Alzheimer’s disease and primary tauopathy diseases. Tauopathy animal models recapitulating the tauopathy such as transgenic, knock-in mouse and rat models have been developed and greatly facilitated the understanding of disease mechanisms. The advance in PET and imaging tracers have enabled non-invasive detection of the accumulation and spread of tau, the associated microglia activation, metabolic, and neurotransmitter receptor alterations in disease animal models. In vivo microPET studies on mouse or rat models of tauopathy have provided significant insights into the phenotypes and time course of pathophysiology of these models and allowed the monitoring of treatment targeting at tau. In this study, we discuss the utilities of PET and recently developed tracers for evaluating the pathophysiology in tauopathy animal models. We point out the outstanding challenges and propose future outlook in visualizing tau-related pathophysiological changes in brain of tauopathy disease animal models.
47
Singh, Aayushi, and Asha Jha. "Cholinesterase Inhibitors Used for the Management of Alzheimer’s Disease: A Review." Journal of Pharmaceutical Research International, December 19, 2021, 121–28. http://dx.doi.org/10.9734/jpri/2021/v33i60a34463.
Full textAbstract:
Alzheimer’s disease (AD) is defined as a progressive neurodegenerative disorder that has lately become the top reason for dementia in the elderly population (usually above 60-65 years). As mentioned before, most AD cases are sporadic and have a late onset. This disease is characterized by impairment of higher cognitive functions like deficits in memory, language comprehension, coordination, etc. The primary pathophysiology behind Alzheimer’s disease is loss of cholinergic innervation due to the formation of neuritic (senile) amyloid-beta plaques and tau protein-containing neurofibrillary tangles (NFTs) in parts of the brain associated with memory functions. These neurofibrillary tangles (NFTs) and amyloid β plaques can cause the induction of other aetiologies of Alzhedisease-likes like neuroinflammation and central hyperexcitability. The brain's main regions affected by Alzheimer’s disease are the neocortex, the basal nucleus of Meynert, and the hippocampus. These areas are associated with higher cognitive functions like memory, arousal, attention, sensory processing, etc. Thus, cholinesterase inhibitors have been widely used as first-line drug therapy for symptomatic relief in Alzheimer’s disease. They function by inhibiting acetylcholinesterase or catabolizing it and henceforth enhancing synaptic availability of Acetylcholine. The commonly prescribed drugs of this class include donepezil, galantamine, physostigmine, metrifonate, and rivastigmine. This article will discuss the widely used cholinesterase inhibitors (old & new) for managing AD symptoms in detail.
48
Fonteh, Alfred N., Abby J. Chiang, Xianghong Arakaki, Sarah P. Edminster, and Michael G. Harrington. "Accumulation of Cerebrospinal Fluid Glycerophospholipids and Sphingolipids in Cognitively Healthy Participants With Alzheimer’s Biomarkers Precedes Lipolysis in the Dementia Stage." Frontiers in Neuroscience 14 (December 16, 2020). http://dx.doi.org/10.3389/fnins.2020.611393.
Full textAbstract:
Insight into lipids’ roles in Alzheimer’s disease (AD) pathophysiology is limited because brain membrane lipids have not been characterized in cognitively healthy (CH) individuals. Since age is a significant risk factor of AD, we hypothesize that aging renders the amyloid precursor protein (APP) more susceptible to abnormal processing because of deteriorating membrane lipids. To reflect brain membranes, we studied their lipid components in cerebrospinal fluid (CSF) and brain-derived CSF nanoparticle membranes. Based on CSF Aβ42/Tau levels established biomarkers of AD, we define a subset of CH participants with normal Aβ42/Tau (CH-NAT) and another group with abnormal or pathological Aβ42/Tau (CH-PAT). We report that glycerophospholipids are differentially metabolized in the CSF supernatant fluid and nanoparticle membrane fractions from CH-NAT, CH-PAT, and AD participants. Phosphatidylcholine molecular species from the supernatant fraction of CH-PAT were higher than in the CH-NAT and AD participants. Sphingomyelin levels in the supernatant fraction were lower in the CH-PAT and AD than in the CH-NAT group. The decrease in sphingomyelin corresponded with an increase in ceramide and dihydroceramide and an increase in the ceramide to sphingomyelin ratio in AD. In contrast to the supernatant fraction, sphingomyelin is higher in the nanoparticle fraction from the CH-PAT group, accompanied by lower ceramide and dihydroceramide and a decrease in the ratio of ceramide to sphingomyelin in CH-PAT compared with CH-NAT. On investigating the mechanism for the lipid changes in AD, we observed that phospholipase A2 (PLA2) activity was higher in the AD group than the CH groups. Paradoxically, acid and neutral sphingomyelinase (SMase) activities were lower in AD compared to the CH groups. Considering external influences on lipids, the clinical groups did not differ in their fasting blood lipids or dietary lipids, consistent with the CSF lipid changes originating from brain pathophysiology. The lipid accumulation in a prodromal AD biomarker positive stage identifies perturbation of lipid metabolism and disturbances in APP/Amyloid beta (Aβ) as early events in AD pathophysiology. Our results identify increased lipid turnover in CH participants with AD biomarkers, switching to a predominantly lipolytic state in dementia. This knowledge may be useful for targeting and testing new AD treatments.
49
Fonteh, Alfred N., Abby J. Chiang, Xianghong Arakaki, Sarah P. Edminster, and Michael G. Harrington. "Accumulation of Cerebrospinal Fluid Glycerophospholipids and Sphingolipids in Cognitively Healthy Participants With Alzheimer’s Biomarkers Precedes Lipolysis in the Dementia Stage." Frontiers in Neuroscience 14 (December 16, 2020). http://dx.doi.org/10.3389/fnins.2020.611393.
Full textAbstract:
Insight into lipids’ roles in Alzheimer’s disease (AD) pathophysiology is limited because brain membrane lipids have not been characterized in cognitively healthy (CH) individuals. Since age is a significant risk factor of AD, we hypothesize that aging renders the amyloid precursor protein (APP) more susceptible to abnormal processing because of deteriorating membrane lipids. To reflect brain membranes, we studied their lipid components in cerebrospinal fluid (CSF) and brain-derived CSF nanoparticle membranes. Based on CSF Aβ42/Tau levels established biomarkers of AD, we define a subset of CH participants with normal Aβ42/Tau (CH-NAT) and another group with abnormal or pathological Aβ42/Tau (CH-PAT). We report that glycerophospholipids are differentially metabolized in the CSF supernatant fluid and nanoparticle membrane fractions from CH-NAT, CH-PAT, and AD participants. Phosphatidylcholine molecular species from the supernatant fraction of CH-PAT were higher than in the CH-NAT and AD participants. Sphingomyelin levels in the supernatant fraction were lower in the CH-PAT and AD than in the CH-NAT group. The decrease in sphingomyelin corresponded with an increase in ceramide and dihydroceramide and an increase in the ceramide to sphingomyelin ratio in AD. In contrast to the supernatant fraction, sphingomyelin is higher in the nanoparticle fraction from the CH-PAT group, accompanied by lower ceramide and dihydroceramide and a decrease in the ratio of ceramide to sphingomyelin in CH-PAT compared with CH-NAT. On investigating the mechanism for the lipid changes in AD, we observed that phospholipase A2 (PLA2) activity was higher in the AD group than the CH groups. Paradoxically, acid and neutral sphingomyelinase (SMase) activities were lower in AD compared to the CH groups. Considering external influences on lipids, the clinical groups did not differ in their fasting blood lipids or dietary lipids, consistent with the CSF lipid changes originating from brain pathophysiology. The lipid accumulation in a prodromal AD biomarker positive stage identifies perturbation of lipid metabolism and disturbances in APP/Amyloid beta (Aβ) as early events in AD pathophysiology. Our results identify increased lipid turnover in CH participants with AD biomarkers, switching to a predominantly lipolytic state in dementia. This knowledge may be useful for targeting and testing new AD treatments.
50
He, Zhijun, Xiaoqian Li, Shuangxue Han, Bingyu Ren, Xia Hu, Nan Li, Xiubo Du, Jiazuan Ni, Xiaogai Yang, and Qiong Liu. "Bis(ethylmaltolato)oxidovanadium (IV) attenuates amyloid-beta-mediated neuroinflammation by inhibiting NF-κB signaling pathway via a PPARγ-dependent mechanism." Metallomics 13, no. 7 (June 14, 2021). http://dx.doi.org/10.1093/mtomcs/mfab036.
Full textAbstract:
Abstract Neuroinflammation plays a pivotal role in the pathophysiology of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. During brain neuroinflammation, activated microglial cells resulting from amyloid-beta (Aβ) overload trigger toxic proinflammatory responses. Bis(ethylmaltolato)oxidovanadium (BEOV) (IV), an important vanadium compound, has been reported to have anti-diabetic, anti-cancer, and neuroprotective effects, but its anti-inflammatory property has rarely been investigated. In the present study, the inhibitory effects of BEOV on neuroinflammation were revealed in both Aβ-stimulated BV2 microglial cell line and APPswe/PS1E9 transgenic mouse brain. BEOV administration significantly decreased the levels of tumor necrosis factor-α, interleukin-6, interleukin-1β, inducible nitric oxide synthase, and cyclooxygenase-2 both in the hippocampus of APPswe/PS1E9 mice and in the Aβ-stimulated BV2 microglia. Furthermore, BEOV suppressed the Aβ-induced activation of nuclear factor-κB (NF-κB) signaling and upregulated the protein expression level of peroxisome proliferator-activated receptor gamma (PPARγ) in a dose-dependent manner. PPARγ inhibitor GW9662 could eliminate the effect of BEOV on Aβ-induced NF-κB activation and proinflammatory mediator production. Taken altogether, these findings suggested that BEOV ameliorates Aβ-stimulated neuroinflammation by inhibiting NF-κB signaling pathway through a PPARγ-dependent mechanism.