Journal articles: 'AMYLOID, APP, ABETA, ALZHEIMER'

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Xie, Zhongcong, Yuanlin Dong, Uta Maeda, Paul Alfille, Deborah J. Culley, Gregory Crosby, and Rudolph E. Tanzi. "The Common Inhalation Anesthetic Isoflurane Induces Apoptosis and Increases Amyloid β Protein Levels." Anesthesiology 104, no. 5 (May 1, 2006): 988–94. http://dx.doi.org/10.1097/00000542-200605000-00015.

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Background The common inhalation anesthetic isoflurane has previously been reported to enhance the aggregation and cytotoxicity of the Alzheimer disease-associated amyloid beta protein (Abeta), the principal peptide component of cerebral beta-amyloid deposits. Methods H4 human neuroglioma cells stably transfected to express human full-length wild-type amyloid precursor protein (APP) were exposed to 2% isoflurane for 6 h. The cells and conditioned media were harvested at the end of the treatment. Caspase-3 activation, processing of APP, cell viability, and Abeta levels were measured with quantitative Western blotting, cell viability kit, and enzyme-linked immunosorbent assay sandwich. The control condition consisted of 5% CO2 plus 21% O2 and balanced nitrogen, which did not affect caspase-3 activation, cell viability, APP processing, or Abeta generation. Results Two percent isoflurane caused apoptosis, altered processing of APP, and increased production of Abeta in H4 human neuroglioma cell lines. Isoflurane-induced apoptosis was independent of changes in Abeta and APP holoprotein levels. However, isoflurane-induced apoptosis was potentiated by increased levels of APP C-terminal fragments. Conclusion A clinically relevant concentration of isoflurane induces apoptosis, alters APP processing, and increases Abeta production in a human neuroglioma cell line. Because altered processing of APP leading to accumulation of Abeta is a key event in the pathogenesis of Alzheimer disease, these findings may have implications for use of this anesthetic agent in individuals with excessive levels of cerebral Abeta and elderly patients at increased risk for postoperative cognitive dysfunction.

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Henriques, A. G., S. I. Vieira, and O. A. B. da Cruz e. Silva. "Abeta Induces Abnormal Cytoskeletal Dynamics which are Reversible Upon Peptide Removal." Microscopy and Microanalysis 18, S5 (August 2012): 23–24. http://dx.doi.org/10.1017/s1431927612012779.

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Alzheimer´s disease (AD) is characterized by extensive neuronal loss in brain areas related to memory and cognitive functions. Central to the neurodegenerative process is a peptide termed Abeta. The latter is the main component of senile plaques, one of the histopathological hallmarks of AD, and derives from proteolytic processing of the Alzheimer´s amyloid precursor protein (APP). Among the alterations induced by Abeta is increased cellular oxidative stress, imbalanced protein phosphorylation and cytoskeletal abnormalities, all factors that contribute to neuronal death.

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Kirkitadze, Marina D., and Anna Kowalska. "Molecular mechanisms initiating amyloid beta-fibril formation in Alzheimer's disease." Acta Biochimica Polonica 52, no. 2 (May 31, 2005): 417–23. http://dx.doi.org/10.18388/abp.2005_3454.

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The deposition of aggregated amyloid beta-protein (Abeta) in the human brain is a major lesion in Alzheimer' disease (AD). The process of Abeta fibril formation is associated with a cascade of neuropathogenic events that induces brain neurodegeneration leading to the cognitive and behavioral decline characteristic of AD. Although a detailed knowledge of Abeta assembly is crucial for the development of new therapeutic approaches, our understanding of the molecular mechanisms underlying the initiation of Abeta fibril formation remains very incomplete. The genetic defects responsible for familial AD influence fibrillogenesis. In a majority of familial cases determined by amyloid precursor protein (APP) and presenilin (PS) mutations, a significant overproduction of Abeta and an increase in the Abeta42/Abeta40 ratio are observed. Recently, it was shown that the two main alloforms of Abeta have distinct biological activity and behaviour at the earliest stage of assembly. In vitro studies demonstrated that Abeta42 monomers, but not Abeta40, form initial and minimal structures (pentamer/hexamer units called paranuclei) that can oligomerize to larger forms. It is now apparent that Abeta oligomers and protofibrils are more neurotoxic than mature Abeta fibrils or amyloid plaques. The neurotoxicity of the prefibrillar aggregates appears to result from their ability to impair fundamental cellular processes by interacting with the cellular membrane, causing oxidative stress and increasing free Ca(2+) that eventually lead to apoptotic cell death.

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Nawrot, Barbara. "Targeting BACE with small inhibitory nucleic acids - a future for Alzheimer's disease therapy?" Acta Biochimica Polonica 51, no. 2 (June 30, 2004): 431–44. http://dx.doi.org/10.18388/abp.2004_3582.

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beta-Secretase, a beta-site amyloid precursor protein (APP) cleaving enzyme (BACE), participates in the secretion of beta-amyloid peptides (Abeta), the major components of the toxic amyloid plaques found in the brains of patients with Alzheimer's disease (AD). According to the amyloid hypothesis, accumulation of Abeta is the primary influence driving AD pathogenesis. Lowering of Abeta secretion can be achieved by decreasing BACE activity rather than by down-regulation of the APP substrate protein. Therefore, beta-secretase is a primary target for anti-amyloid therapeutic drug design. Several approaches have been undertaken to find an effective inhibitor of human beta-secretase activity, mostly in the field of peptidomimetic, non-cleavable substrate analogues. This review describes strategies targeting BACE mRNA recognition and its down-regulation based on the antisense action of small inhibitory nucleic acids (siNAs). These include antisense oligonucleotides, catalytic nucleic acids - ribozymes and deoxyribozymes - as well as small interfering RNAs (siRNAs). While antisense oligonucleotides were first used to identify an aspartyl protease with beta-secretase activity, all the strategies now demonstrate that siNAs are able to inhibit BACE gene expression in a sequence-specific manner, measured both at the level of its mRNA and at the level of protein. Moreover, knock-down of BACE reduces the intra- and extracellular population of Abeta40 and Abeta42 peptides. An anti-amyloid effect of siNAs is observed in a wide spectrum of cell lines as well as in primary cortical neurons. Thus targeting BACE with small inhibitory nucleic acids may be beneficial for the treatment of Alzheimer's disease and for future drug design.

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Tanghe, An, Annelies Termont, Pascal Merchiers, Stephan Schilling, Hans-Ulrich Demuth, Louise Scrocchi, Fred Van Leuven, Gerard Griffioen, and Tom Van Dooren. "Pathological Hallmarks, Clinical Parallels, and Value for Drug Testing in Alzheimer's Disease of the APP[V717I] London Transgenic Mouse Model." International Journal of Alzheimer's Disease 2010 (2010): 1–9. http://dx.doi.org/10.4061/2010/417314.

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The APP[V717I] London (APP-Ld) mouse model recapitulates important pathological and clinical hallmarks of Alzheimer's disease (AD) and is therefore a valuable paradigm for evaluating therapeutic candidates. Historically, both the parenchymal and vascular amyloid deposits, and more recently, truncated and pyroglutamate-modified Abet species, are perceived as important hallmarks of AD-pathology. Late stage symptoms are preceded by robust deficits in orientation and memory that correlate in time with Abeta oligomerization and GSK3-mediated phosphorylation of endogenous murine Tau, all markers that have gained considerable interest during the last decade. Clinical parallels with AD patients and the value of the APP-Ld transgenic mouse model for preclinicalin vivotesting of candidate drugs are discussed.

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Tadic, Jelena, Julia Ring, Andrea Jerkovic, Selena Ristic, Marta Maglione, Jörn Dengjel, Stephan J. Sigrist, and Tobias Eisenberg. "A pathological role of the Hsp40 protein Ydj1/DnaJA1 in models of Alzheimer’s disease." Cell Stress 6, no. 5 (May 9, 2022): 61–64. http://dx.doi.org/10.15698/cst2022.05.267.

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Alzheimer’s disease (AD) is the most common form of dementia with millions of people affected worldwide. Pathophysiological manifestations of AD include the extracellular accumulation of amyloid beta (Abeta) pep-tides, products of the proteolytic cleavage of the amy-loid precursor protein APP. Increasing evidence sug-gests that Abeta peptides also accumulate intracellular-ly, triggering neurotoxic events such as mitochondrial dysfunction. However, the molecular factors driving formation and toxicity of intracellular Abeta are poorly understood. In our recent study [EMBO Mol Med 2022 – e13952], we used different eukaryotic model systems to identify such factors. Based on a genetic screen in yeast and subsequent molecular analyses, we found that both the yeast chaperone Ydj1 and its human ortholog DnaJA1 physically interact with Abeta, facili-tate the aggregation of Abeta peptides into small oli-gomers and promote their translocation to mitochon-dria. Deletion or downregulation of this chaperone pro-tected from Abeta-mediated toxicity in yeast and Dro-sophila AD models, respectively. Most importantly, the identified chaperone is found to be dysregulated in post-mortem human samples of AD patients. Here, we aim to outline our key findings, highlighting pathological functions of a heat shock protein (Hsp) family member, which are generally considered protective rather than toxic during neurodegeneration. Our results thus chal-lenge the concept of developing generalized chaperone activation-based therapies and call for carefully consid-ering also maladaptive functions of specific heat shock proteins.

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Chalimoniuk, Małgorzata, Anna Stolecka, Magdalena Cakała, Susane Hauptmann, Kris Schulz, Uta Lipka, Kristine Leuner, Anne Eckert, Walter E. Muller, and Joanna B. Strosznajder. "Amyloid beta enhances cytosolic phospholipase A2 level and arachidonic acid release via nitric oxide in APP-transfected PC12 cells." Acta Biochimica Polonica 54, no. 3 (August 23, 2007): 611–23. http://dx.doi.org/10.18388/abp.2007_3235.

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Cytosolic phospholipase A2 (cPLA2) preferentially liberates arachidonic acid (AA), which is known to be elevated in Alzheimer's disease (AD). The aim of this study was to investigate the possible relationship between enhanced nitric oxide (NO) generation observed in AD and cPLA2 protein level, phosphorylation, and AA release in rat pheochromocytoma cell lines (PC12) differing in amyloid beta secretion. PC12 control cells, PC12 cells bearing the Swedish double mutation in amyloid beta precursor protein (APPsw), and PC12 cells transfected with human APP (APPwt) were used. The transfected APPwt and APPsw PC12 cells showed an about 2.8- and 4.8-fold increase of amyloid beta (Abeta) secretion comparing to control PC12 cells. An increase of NO synthase activity, cGMP and free radical levels in APPsw and APPwt PC12 cells was observed. cPLA2 protein level was higher in APPsw and APPwt PC12 cells comparing to PC12 cells. Moreover, phosphorylated cPLA2 protein level and [3H]AA release were also higher in APP-transfected PC12 cells than in the control PC12 cells. An NO donor, sodium nitroprusside, stimulated [3H]AA release from prelabeled cells. The highest NO-induced AA release was observed in control PC12 cells, the effect in the other cell lines being statistically insignificant. Inhibition of cPLA2 by AACOCF3 significantly decreased the AA release. Inhibitors of nNOS and gamma-secretase reduced AA release in APPsw and APPwt PC12 cells. The basal cytosolic [Ca2+](i) and mitochondrial Ca2+ concentration was not changed in all investigated cell lines. Stimulation with thapsigargin increased the cytosolic and mitochondrial Ca2+ level, activated NOS and stimulated AA release in APP-transfected PC12 cells. These results indicate that Abeta peptides enhance the protein level and phosphorylation of cPLA2 and AA release by the NO signaling pathway.

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Bathini, Praveen, Tao Sun, Mathias Schenk, Stephan Schilling, Nathan J. McDannold, and Cynthia A. Lemere. "Acute Effects of Focused Ultrasound-Induced Blood-Brain Barrier Opening on Anti-Pyroglu3 Abeta Antibody Delivery and Immune Responses." Biomolecules 12, no. 7 (July 6, 2022): 951. http://dx.doi.org/10.3390/biom12070951.

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Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS is limited due to the blood-brain-barrier (BBB). Focused ultrasound (FUS) is a method to induce a temporary opening of the BBB to enhance the delivery of therapeutic agents to the CNS. In this study, we evaluated the acute effects of FUS and whether the use of FUS-induced BBB opening enhances the delivery of 07/2a mAb, an anti-pyroglutamate-3 Aβ antibody, in aged 24 mo-old APP/PS1dE9 transgenic mice. FUS was performed either unilaterally or bilaterally with mAb infusion and the short-term effect was analyzed 4 h and 72 h post-treatment. Quantitative analysis by ELISA showed a 5–6-fold increase in 07/2a mAb levels in the brain at both time points and an increased brain-to-blood ratio of the antibody. Immunohistochemistry demonstrated an increase in IgG2a mAb detection particularly in the cortex, enhanced immunoreactivity of resident Iba1+ and phagocytic CD68+ microglial cells, and a transient increase in the infiltration of Ly6G+ immune cells. Cerebral microbleeds were not altered in the unilaterally or bilaterally sonicated hemispheres. Overall, this study shows the potential of FUS therapy for the enhanced delivery of CNS therapeutics.

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Juszczyk, Paulina, Aleksandra S. Kołodziejczyk, and Zbigniew Grzonka. "Circular dichroism and aggregation studies of amyloid beta (11-8) fragment and its variants." Acta Biochimica Polonica 52, no. 2 (June 25, 2005): 425–31. http://dx.doi.org/10.18388/abp.2005_3455.

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Aggregation of Abeta peptides is a seminal event in Alzheimer's disease. Detailed understanding of Abeta assembly would facilitate the targeting and design of fibrillogenesis inhibitors. Here comparative conformational and aggregation studies using CD spectroscopy and thioflavine T fluorescence assay are presented. As a model peptide, the 11-28 fragment of Abeta was used. This model peptide is known to contain the core region responsible for Abeta aggregation. The structural and aggregational behaviour of the peptide was compared with the properties of its variants corresponding to natural, clinically relevant mutants at positions 21-23 (A21G, E22K, E22G, E22Q and D23N). In HFIP (hexafluoro-2-propanol), a strong alpha-helix inducer, the CD spectra revealed an unexpectedly high amount of beta-sheet conformation. The aggregation process of Abeta(11-28) variants provoked by water addition to HFIP was found to be consistent with a model of an alpha-helix-containing intermediate. The aggregation propensity of all Abeta(11-28) variants was also compared and discussed.

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Ramakrishna, Narayan, Marilyn Smedman, and Bruce Gillam. "Suppression of Alzheimer Amyloid Precursor Protein (APP) Expression by Exogenous APP mRNA." Archives of Biochemistry and Biophysics 326, no. 2 (February 1996): 243–51. http://dx.doi.org/10.1006/abbi.1996.0072.

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De Strooper, B., and W. Annaert. "Proteolytic processing and cell biological functions of the amyloid precursor protein." Journal of Cell Science 113, no. 11 (June 1, 2000): 1857–70. http://dx.doi.org/10.1242/jcs.113.11.1857.

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Recent research has identified some key players involved in the proteolytic processing of amyloid precursor protein (APP) to amyloid beta-peptide, the principal component of the amyloid plaques in Alzheimer patients. Interesting parallels exists with the proteolysis of other proteins involved in cell differentiation, cholesterol homeostasis and stress responses. Since the cytoplasmic domain of APP is anchored to a complex protein network that might function in axonal elongation, dendritic arborisation and neuronal cell migration, the proteolysis of APP might be critically involved in intracellular signalling events.

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Nizzari, Mario, Stefano Thellung, Alessandro Corsaro, Valentina Villa, Aldo Pagano, Carola Porcile, Claudio Russo, and Tullio Florio. "Neurodegeneration in Alzheimer Disease: Role of Amyloid Precursor Protein and Presenilin 1 Intracellular Signaling." Journal of Toxicology 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/187297.

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Alzheimer disease (AD) is a heterogeneous neurodegenerative disorder characterized by (1) progressive loss of synapses and neurons, (2) intracellular neurofibrillary tangles, composed of hyperphosphorylated Tau protein, and (3) amyloid plaques. Genetically, AD is linked to mutations in few proteins amyloid precursor protein (APP) and presenilin 1 and 2 (PS1 and PS2). The molecular mechanisms underlying neurodegeneration in AD as well as the physiological function of APP are not yet known. A recent theory has proposed that APP and PS1 modulate intracellular signals to induce cell-cycle abnormalities responsible for neuronal death and possibly amyloid deposition. This hypothesis is supported by the presence of a complex network of proteins, clearly involved in the regulation of signal transduction mechanisms that interact with both APP and PS1. In this review we discuss the significance of novel finding related to cell-signaling events modulated by APP and PS1 in the development of neurodegeneration.

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Ehehalt, Robert, Patrick Keller, Christian Haass, Christoph Thiele, and Kai Simons. "Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts." Journal of Cell Biology 160, no. 1 (January 6, 2003): 113–23. http://dx.doi.org/10.1083/jcb.200207113.

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Formation of senile plaques containing the β-amyloid peptide (Aβ) derived from the amyloid precursor protein (APP) is an invariant feature of Alzheimer's disease (AD). APP is cleaved either by β-secretase or by α-secretase to initiate amyloidogenic (release of Aβ) or nonamyloidogenic processing of APP, respectively. A key to understanding AD is to unravel how access of these enzymes to APP is regulated. Here, we demonstrate that lipid rafts are critically involved in regulating Aβ generation. Reducing cholesterol levels in N2a cells decreased Aβ production. APP and the β-site APP cleavage enzyme (BACE1) could be induced to copatch at the plasma membrane upon cross-linking with antibodies and to segregate away from nonraft markers. Antibody cross-linking dramatically increased production of Aβ in a cholesterol-dependent manner. Aβ generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTPase-activating protein, RN-tre. This inhibition could be overcome by antibody cross-linking. These observations suggest the existence of two APP pools. Although APP inside raft clusters seems to be cleaved by β-secretase, APP outside rafts undergoes cleavage by α-secretase. Thus, access of α- and β-secretase to APP, and therefore Aβ generation, may be determined by dynamic interactions of APP with lipid rafts.

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Guyant-Maréchal, L. "APP locus duplication causes Alzheimer disease with cerebral amyloid angiopathy." Journal of the Neurological Sciences 283, no. 1-2 (August 2009): 270. http://dx.doi.org/10.1016/j.jns.2009.02.119.

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Du, Ying, Yingjun Zhao, Chuan Li, Qiuyang Zheng, Jing Tian, Zhuyi Li, Timothy Y. Huang, Wei Zhang, and Huaxi Xu. "Inhibition of PKCδ reduces amyloid-β levels and reverses Alzheimer disease phenotypes." Journal of Experimental Medicine 215, no. 6 (May 8, 2018): 1665–77. http://dx.doi.org/10.1084/jem.20171193.

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β-amyloid protein (Aβ) plays a central role in the pathogenesis of Alzheimer disease (AD). Aβ is generated from sequential cleavage of amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. Although activation of some protein kinase C (PKC) isoforms such as PKCα and ε has been shown to regulate nonamyloidogenic pathways and Aβ degradation, it is unclear whether other PKC isoforms are involved in APP processing/AD pathogenesis. In this study, we report that increased PKCδ levels correlate with BACE1 expression in the AD brain. PKCδ knockdown reduces BACE1 expression, BACE1-mediated APP processing, and Aβ production. Conversely, overexpression of PKCδ increases BACE1 expression and Aβ generation. Importantly, inhibition of PKCδ by rottlerin markedly reduces BACE1 expression, Aβ levels, and neuritic plaque formation and rescues cognitive deficits in an APP Swedish mutations K594N/M595L/presenilin-1 with an exon 9 deletion–transgenic AD mouse model. Our study indicates that PKCδ plays an important role in aggravating AD pathogenesis, and PKCδ may be a potential target in AD therapeutics.

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Grangeon, Lou, Kévin Cassinari, Stéphane Rousseau, Bernard Croisile, Maïté Formaglio, Olivier Moreaud, Jean Boutonnat, et al. "Early-Onset Cerebral Amyloid Angiopathy and Alzheimer Disease Related to an APP Locus Triplication." Neurology Genetics 7, no. 5 (September 8, 2021): e609. http://dx.doi.org/10.1212/nxg.0000000000000609.

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Background and ObjectiveTo report a triplication of the amyloid-β precursor protein (APP) locus along with relative messenger RNA (mRNA) expression in a family with autosomal dominant early-onset cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD).MethodsFour copies of the APP gene were identified by quantitative multiplex PCR of short fluorescent fragments, fluorescent in situ hybridization (FISH), and array comparative genomic hybridization. APP mRNA levels were assessed using reverse-transcription–digital droplet PCR in the proband's whole blood and compared with 10 controls and 9 APP duplication carriers.ResultsBeginning at age 39 years, the proband developed severe episodic memory deficits with a CSF biomarker profile typical of AD and multiple lobar microbleeds in the posterior regions on brain MRI. His father had seizures and recurrent cerebral hemorrhage since the age of 37 years. His cerebral biopsy showed abundant perivascular amyloid deposits, leading to a diagnosis of CAA. In the proband, we identified 4 copies of a 506-kb region located on chromosome 21q21.3 and encompassing the whole APP gene without any other gene. FISH suggested that the genotype of the proband was 3 copies/1 copy corresponding to an APP locus triplication, which was consistent with the presence of 2 APP copies in the healthy mother and with the paternal medical history. Analysis of the APP mRNA level showed a 2-fold increase in the proband and a 1.8 fold increase in APP duplication carriers compared with controls.DiscussionIncreased copy number of APP is sufficient to cause AD and CAA, with likely earlier onset in case of triplication compared with duplication.

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Imbimbo, Bruno P., Ugo Lucca, and Mark Watling. "Can Anti–β-amyloid Monoclonal Antibodies Work in Autosomal Dominant Alzheimer Disease?" Neurology Genetics 7, no. 1 (December 17, 2020): e535. http://dx.doi.org/10.1212/nxg.0000000000000535.

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The dominant theory of Alzheimer disease (AD) has been that amyloid-β (Aβ) accumulation in the brain is the initial cause of the degeneration leading to cognitive and functional deficits. Autosomal dominant Alzheimer disease (ADAD), in which pathologic mutations of the amyloid precursor protein (APP) or presenilins (PSENs) genes are known to cause abnormalities of Aβ metabolism, should thus offer perhaps the best opportunity to test anti-Aβ drugs. Two long-term preventive studies (Dominantly Inherited Alzheimer Network Trials Unit Adaptive Prevention Trial [DIAN-TU-APT] and Alzheimer Preventive Initiative–ADAD) were set up to evaluate the efficacy of monoclonal anti-Aβ antibodies (solanezumab, gantenerumab, and crenezumab) in carriers of ADAD, but the results of the DIAN-TU-APT study have shown that neither solanezumab nor gantenerumab slowed cognitive decline in 144 subjects with ADAD followed for 4 years, despite one of the drugs (gantenerumab) significantly affected biomarkers relevant to their intended mechanism of action. Surprisingly, solanezumab significantly accelerated cognitive decline of both asymptomatic and symptomatic subjects. These failures further undermine the Aβ hypothesis and could support the suggestion that ADAD is triggered by accumulation of other APP metabolites, rather than Aβ.

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Sabo, Shasta L., Annat F. Ikin, Joseph D. Buxbaum, and Paul Greengard. "The Alzheimer Amyloid Precursor Protein (APP) and Fe65, an APP-Binding Protein, Regulate Cell Movement." Journal of Cell Biology 153, no. 7 (June 18, 2001): 1403–14. http://dx.doi.org/10.1083/jcb.153.7.1403.

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FE65 binds to the Alzheimer amyloid precursor protein (APP), but the function of this interaction has not been identified. Here, we report that APP and FE65 are involved in regulation of cell movement. APP and FE65 colocalize with actin and Mena, an Abl-associated signaling protein thought to regulate actin dynamics, in lamellipodia. APP and FE65 specifically concentrate with β1-integrin in dynamic adhesion sites known as focal complexes, but not in more static adhesion sites known as focal adhesions. Overexpression of APP accelerates cell migration in an MDCK cell wound–healing assay. Coexpression of APP and FE65 dramatically enhances the effect of APP on cell movement, probably by regulating the amount of APP at the cell surface. These data are consistent with a role for FE65 and APP, possibly in a Mena-containing macromolecular complex, in regulation of actin-based motility.

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BORCHARDT, Thilo, James CAMAKARIS, Roberto CAPPAI, Colin L. MASTERS, Konrad BEYREUTHER, and Gerd MULTHAUP. "Copper inhibits β-amyloid production and stimulates the non-amyloidogenic pathway of amyloid-precursor-protein secretion." Biochemical Journal 344, no. 2 (November 24, 1999): 461–67. http://dx.doi.org/10.1042/bj3440461.

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Previous studies have demonstrated that amyloid precursor protein (APP) can bind and reduce Cu(II) to Cu(I), leading to oxidative modification of APP. In the present study we show that adding copper to Chinese-hamster ovary (CHO) cells greatly reduced the levels of amyloid Aβ peptide (Aβ) both in parental CHO-K1 and in copper-resistant CHO-CUR3 cells, which have lower intracellular copper levels. Copper also caused an increase in the secretion of the APP ectodomain, indicating that the large decrease in Aβ release was not due to a general inhibition in protein secretion. There was an increase in intracellular full-length APP levels which paralleled the decrease in Aβ generation, suggesting the existence of two distinct regulating mechanisms, one acting on Aβ production and the other on APP synthesis. Maximal inhibition of Aβ production and stimulation of APP secretion was achieved in CHO-K1 cells at about 10 μM copper and in CHO-CUR3 cells at about 50 μM copper. This dose ‘window of opportunity’ at which copper promoted the non-amyloidogenic pathway of APP was confirmed by an increase in the non-amyloidogenic p3 fragment produced by α-secretase cleavage. Our findings suggest that copper or copper agonists might be useful tools to discover novel targets for anti-Alzheimer drugs and may prove beneficial for the prevention of Alzheimer's disease.

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Miles, Luke, Gabriela Crespi, Tracy Nero, and Michael Parker. "Structural biology of Alzheimer's disease." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C698. http://dx.doi.org/10.1107/s2053273314093012.

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Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in humans with age being the biggest risk factor. The mechanisms by which the disease progresses to cognitive decline in the sufferer are complex and not fully elucidated. A defining pathological feature is the deposition of extracellular plaques composed primarily of misfolded amyloid beta (Aβ) peptide: a proteolytic breakdown product of the much larger Amyloid Precursor Protein. While Aβ peptides are the main constituents of amyloid plaques that burden the diseased brain, plaque burden correlates poorly with the severity of the disease. There is accumulating evidence that a prefibrillar or protofibrillar soluble form of Aβ can compromise neuronal functions and trigger cell death. Immunotherapy targeting Abeta is a promising direction in AD research with active and passive immunotherapies shown to lower cerebral Aβ levels and rescue cognitive function in animal models. Anti-Aβ immunotherapies are a significant class of AD therapeutics currently in human clinical trials. We have been examining the molecular basis of antibody engagement of Aβ epitopes to inform the analysis of clinical trial data and to guide the engineering of anti-Aβ antibodies with optimised specificity and affinity. We have determined the structures of three different AD antibodies in complex with Ab peptides: (1) WO2, which recognises the N-terminus of Aβ, (2) Mab 2286, which like the AD immunotherapeutic Ponezumab (Pfizer), shows specificity for the C-terminus of Aβ40 but has no significant cross-reactivity with Aβ42/43, and (3) Bapineuzumab, a humanized antibody developed by Pfizer and Johnson & Johnson which recognises the N-terminus of Aβ but cannot recognize N-terminally modified or truncated Aβ peptides (1). All these studies reveal surprising aspects of Aβ peptide recognition by the antibodies and suggest new avenues for AD antibody development.

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Tzeng, Te-Chen, Yuto Hasegawa, Risa Iguchi, Amy Cheung, Daniel R. Caffrey, Elizabeth Jeanne Thatcher, Wenjie Mao, et al. "Inflammasome-derived cytokine IL18 suppresses amyloid-induced seizures in Alzheimer-prone mice." Proceedings of the National Academy of Sciences 115, no. 36 (August 20, 2018): 9002–7. http://dx.doi.org/10.1073/pnas.1801802115.

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Alzheimer’s disease (AD) is characterized by the progressive destruction and dysfunction of central neurons. AD patients commonly have unprovoked seizures compared with age-matched controls. Amyloid peptide-related inflammation is thought to be an important aspect of AD pathogenesis. We previously reported that NLRP3 inflammasome KO mice, when bred into APPswe/PS1ΔE9 (APP/PS1) mice, are completely protected from amyloid-induced AD-like disease, presumably because they cannot produce mature IL1β or IL18. To test the role of IL18, we bred IL18KO mice with APP/PS1 mice. Surprisingly, IL18KO/APP/PS1 mice developed a lethal seizure disorder that was completely reversed by the anticonvulsant levetiracetam. IL18-deficient AD mice showed a lower threshold in chemically induced seizures and a selective increase in gene expression related to increased neuronal activity. IL18-deficient AD mice exhibited increased excitatory synaptic proteins, spine density, and basal excitatory synaptic transmission that contributed to seizure activity. This study identifies a role for IL18 in suppressing aberrant neuronal transmission in AD.

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Rani, Pratibha, Kamaldeep Singh, Anania Arjuna, and Savita Devi. "GENETIC DISORDER ALZHEIMER." Asian Journal of Pharmaceutical and Clinical Research 10, no. 12 (December 1, 2017): 36. http://dx.doi.org/10.22159/ajpcr.2017.v10i12.18684.

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Alzheimer’s disease (AD), slowly continuous neurological disorder, mostly appears in older >65 age that deals with the memory loss due to death or damage of brain cells and cognitive functions (thinking, reasoning, and behavior abnormalities) due to the accumulation of the specific protein (beta-amyloid protein) which form plaque and fibers (tau tangles) in the brain. Not only the genetic factors are responsible but also most of the non-genetic factors are responsible for AD. Several mutations in the gene (APP, APOE, PENS1, PENS2 on chromosome no. 21, 19, 14, 1) are responsible for causing four types of AD. Memory loss is most common sign of AD. Predisposing factors of AD are hereditary, severe brain injury or traumatic, and metabolic diseases such as diabetes mellitus, hypercholesteremia, and obesity. Although treatment can manage some symptoms in few people, but there is no current mechanism to cure AD or stop its progression. Beta-secretase inhibitor molecule prevents the first step in a chain accumulation which leads to the formation of amyloid plaque in the brain. However, the scientist or researchers have established a compound NIC5-15 they have been found NIC5-15 has safe and effectual treatment which has been used to stabilize cognitive performance in patients with mild to moderate AD.

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Mori, Takashi, Naoki Koyama, Tatsuya Segawa, Masahiro Maeda, Nobuhiro Maruyama, Noriaki Kinoshita, Huayan Hou, Jun Tan, and Terrence Town. "Methylene Blue Modulates β-Secretase, Reverses Cerebral Amyloidosis, and Improves Cognition in Transgenic Mice." Journal of Biological Chemistry 289, no. 44 (August 25, 2014): 30303–17. http://dx.doi.org/10.1074/jbc.m114.568212.

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Amyloid precursor protein (APP) proteolysis is required for production of amyloid-β (Aβ) peptides that comprise β-amyloid plaques in the brains of patients with Alzheimer disease (AD). Here, we tested whether the experimental agent methylene blue (MB), used for treatment of methemoglobinemia, might improve AD-like pathology and behavioral deficits. We orally administered MB to the aged transgenic PSAPP mouse model of cerebral amyloidosis and evaluated cognitive function and cerebral amyloid pathology. Beginning at 15 months of age, animals were gavaged with MB (3 mg/kg) or vehicle once daily for 3 months. MB treatment significantly prevented transgene-associated behavioral impairment, including hyperactivity, decreased object recognition, and defective spatial working and reference memory, but it did not alter nontransgenic mouse behavior. Moreover, brain parenchymal and cerebral vascular β-amyloid deposits as well as levels of various Aβ species, including oligomers, were mitigated in MB-treated PSAPP mice. These effects occurred with inhibition of amyloidogenic APP proteolysis. Specifically, β-carboxyl-terminal APP fragment and β-site APP cleaving enzyme 1 protein expression and activity were attenuated. Additionally, treatment of Chinese hamster ovary cells overexpressing human wild-type APP with MB significantly decreased Aβ production and amyloidogenic APP proteolysis. These results underscore the potential for oral MB treatment against AD-related cerebral amyloidosis by modulating the amyloidogenic pathway.

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Ledoux, S., N. Rebai, A. Dagenais, I. T. Shaw, J. Nalbantoglu, R. P. Sekaly, and N. R. Cashman. "Amyloid precursor protein in peripheral mononuclear cells is up-regulated with cell activation." Journal of Immunology 150, no. 12 (June 15, 1993): 5566–75. http://dx.doi.org/10.4049/jimmunol.150.12.5566.

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Abstract The deposition of beta/A4 protein in extraneural organs of patients with Alzheimer disease suggests that this peptide may in part be derived from a peripheral precursor. We studied expression of amyloid precursor protein (APP) in PBMC. APP expression was detectable in resting PBMC by northern blot analysis, immunoblotting studies, and immunohistochemistry. By reverse transcription-polymerase chain reaction, the 751 and 770 APP transcripts containing the Kunitz protease inhibitor (KPI) domain were approximately 10-fold more abundant than the 695 transcript lacking the KPI domain. Activation of PBMC with the lectin PHA-P was associated with an increase in apparent intracellular APP content by cytofluorometry, and an increase in the proportion of the 695 APP transcript lacking the KPI domain. We conclude that resting and activated PBMC express APP and could contribute to a circulating pool of this protein. In addition, PBMC APP is up-regulated with mitogenic stimulation and may participate in the regulation of activation of these cells.

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Borgegard, Tomas, Anders Juréus, Fredrik Olsson, Susanne Rosqvist, Alan Sabirsh, Didier Rotticci, Kim Paulsen, et al. "First and Second Generation γ-Secretase Modulators (GSMs) Modulate Amyloid-β (Aβ) Peptide Production through Different Mechanisms." Journal of Biological Chemistry 287, no. 15 (February 13, 2012): 11810–19. http://dx.doi.org/10.1074/jbc.m111.305227.

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γ-Secretase-mediated cleavage of amyloid precursor protein (APP) results in the production of Alzheimer disease-related amyloid-β (Aβ) peptides. The Aβ42 peptide in particular plays a pivotal role in Alzheimer disease pathogenesis and represents a major drug target. Several γ-secretase modulators (GSMs), such as the nonsteroidal anti-inflammatory drugs (R)-flurbiprofen and sulindac sulfide, have been suggested to modulate the Alzheimer-related Aβ production by targeting the APP. Here, we describe novel GSMs that are selective for Aβ modulation and do not impair processing of Notch, EphB2, or EphA4. The GSMs modulate Aβ both in cell and cell-free systems as well as lower amyloidogenic Aβ42 levels in the mouse brain. Both radioligand binding and cellular cross-competition experiments reveal a competitive relationship between the AstraZeneca (AZ) GSMs and the established second generation GSM, E2012, but a noncompetitive interaction between AZ GSMs and the first generation GSMs (R)-flurbiprofen and sulindac sulfide. The binding of a 3H-labeled AZ GSM analog does not co-localize with APP but overlaps anatomically with a γ-secretase targeting inhibitor in rodent brains. Combined, these data provide compelling evidence of a growing class of in vivo active GSMs, which are selective for Aβ modulation and have a different mechanism of action compared with the original class of GSMs described.

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Huttunen, Henri J., Suzanne Y. Guénette, Camilla Peach, Christopher Greco, Weiming Xia, Doo Yeon Kim, Cory Barren, Rudolph E. Tanzi, and Dora M. Kovacs. "HtrA2 Regulates β-Amyloid Precursor Protein (APP) Metabolism through Endoplasmic Reticulum-associated Degradation." Journal of Biological Chemistry 282, no. 38 (August 6, 2007): 28285–95. http://dx.doi.org/10.1074/jbc.m702951200.

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Alzheimer disease-associated β-amyloid peptide is generated from its precursor protein APP. By using the yeast two-hybrid assay, here we identified HtrA2/Omi, a stress-responsive chaperone-protease as a protein binding to the N-terminal cysteinerich region of APP. HtrA2 coimmunoprecipitates exclusively with immature APP from cell lysates as well as mouse brain extracts and degrades APP in vitro. A subpopulation of HtrA2 localizes to the cytosolic side of the endoplasmic reticulum (ER) membrane where it contributes to ER-associated degradation of APP together with the proteasome. Inhibition of the proteasome results in accumulation of retrotranslocated forms of APP and increased association of APP with HtrA2 and Derlin-1 in microsomal membranes. In cells lacking HtrA2, APP holoprotein is stabilized and accumulates in the early secretory pathway correlating with elevated levels of APP C-terminal fragments and increased Aβ secretion. Inhibition of ER-associated degradation (either HtrA2 or proteasome) promotes binding of APP to the COPII protein Sec23 suggesting enhanced trafficking of APP out of the ER. Based on these results we suggest a novel function for HtrA2 as a regulator of APP metabolism through ER-associated degradation.

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Liu, Huan, Tian Tian, Shanchun Qin, Wen Li, Xumei Zhang, Xuan Wang, Yuxia Gao, and Guowei Huang. "Folic acid deficiency enhances abeta accumulation in APP/PS1 mice brain and decreases amyloid-associated miRNAs expression." Journal of Nutritional Biochemistry 26, no. 12 (December 2015): 1502–8. http://dx.doi.org/10.1016/j.jnutbio.2015.07.020.

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Babylon, Lukas, Fabian Schmitt, Yannik Franke, Tim Hubert, and Gunter P. Eckert. "Effects of Combining Biofactors on Bioenergetic Parameters, Aβ Levels and Survival in Alzheimer Model Organisms." International Journal of Molecular Sciences 23, no. 15 (August 4, 2022): 8670. http://dx.doi.org/10.3390/ijms23158670.

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Increased amyloid beta (Aβ) levels and mitochondrial dysfunction (MD) in the human brain characterize Alzheimer disease (AD). Folic acid, magnesium and vitamin B6 are essential micro-nutrients that may provide neuroprotection. Bioenergetic parameters and amyloid precursor protein (APP) processing products were investigated in vitro in human neuroblastoma SH-SY5Y-APP695 cells, expressing neuronal APP, and in vivo, in the invertebrate Caenorhabditis elegans (CL2006 & GMC101) expressing muscular APP. Model organisms were incubated with either folic acid and magnesium-orotate (ID63) or folic acid, magnesium-orotate and vitamin B6 (ID64) in different concentrations. ID63 and ID64 reduced Aβ, soluble alpha APP (sAPPα), and lactate levels in SH-SY5Y-APP695 cells. The latter might be explained by enhanced expression of lactate dehydrogenase (LDHA). Micronutrient combinations had no effects on mitochondrial parameters in SH-SY5Y-APP695 cells. ID64 showed a significant life-prolonging effect in C. elegans CL2006. Incubation of GMC101 with ID63 significantly lowered Aβ aggregation. Both combinations significantly reduced paralysis and thus improved the phenotype in GMC101. Thus, the combinations of the tested biofactors are effective in pre-clinical models of AD by interfering with Aβ related pathways and glycolysis.

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Clark, Arthur W., and Irma M. Parhad. "Expression of Neuronal mRNAs in Alzheimer Type Degeneration of the Nervous System." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 16, S4 (November 1989): 477–82. http://dx.doi.org/10.1017/s0317167100029802.

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ABSTRACT:There is extensive evidence for decrements of gene expression in AD, at several levels in the process. There is also evidence for increments of expression of some genes. Message for the amyloid precursor protein (APP), for example, is elevated in surviving neurons of certain subcortical populations in AD. We evaluated expression of message for APP as well as for certain neuronal and glial cytoskeletal proteins in the cortex of six cases of AD. Neuronal mRNAs, including that for APP, were significantly decreased when compared with control cortex, whereas the glial mRNA was increased. We have projected studies to determine the evolution of these mRNA decrements in Alzheimer-type degeneration. The rationale for these studies and preliminary findings are discussed.

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Probst, Botez, and Tolnay. "Neuropathology of Alzheimer’s disease." Therapeutische Umschau 56, no. 2 (February 1, 1999): 88–93. http://dx.doi.org/10.1024/0040-5930.56.2.88.

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Ziel dieser Übersichtsarbeit ist eine Schilderung der Morphologie und eine Darstellung einzelner pathogenetischer Faktoren der Alzheimer Krankheit (AK). Die Übersicht beinhaltet weiter eine Beschreibung der Silberkornkrankheit, einer häufigen, mit der AK verwandten, jedoch noch weitgehend verkannten Demenzursache des hohen Alters. Makroskopisch zeigt das Gehirn eines an AK Verstorbenen vor allem eine Atrophie des medialen Temporallappens, wobei die Hippocampi, die Entorhinalrinde und die Mandelkerne besonders stark betroffen sind. Histologische Merkmale der AK sind: ein regionalspezifischer Neuronenverlust, eine Verminderung der kortikalen Synapsendichte sowie intra- und extrazelluläre Ablagerungen abnormer Proteine. Die intraneuronale Ansammlung abnormer fibrillärer Strukturen, die vor allem auf die Hyperphosphorylierung des Zytoskelett-assoziierten Proteins Tau zurückzuführen ist, beeinträchtigt die Funktion der betroffenen Nervenzellen und ist für deren Untergang mitverantwortlich. Die Ausbreitung dieser Veränderungen über den Hippocampus hinaus auf den gesamten Neokortex führt zur Alzheimer-Demenz. Die extrazelluläre Ablagerung von Abeta-Amyloid im Neuropil (senile Plaques) ist bei der AK besonders stark ausgeprägt. Zwischen der Gesamtzahl kortikaler Plaques und klinischen Parametern der Demenz besteht offenbar keine klare Korrelation. Eine solche findet sich jedoch bezüglich des Anteils neuritischer Plaques, d.h. des Ausmaßes an neuritischer Degeneration innerhalb seniler Plaques. Die Übersicht beinhaltet weiter eine kurze Schilderung der kongophilen Angiopathie und der Alzheimer-assoziierten Veränderungen der cholinergischen Innervation des Gehirns. Schließlich werden die genetischen Risikofaktoren der AK diskutiert.

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Wiley, Jesse C., Elise A. Smith, Mark P. Hudson, Warren C. Ladiges, and Mark Bothwell. "Fe65 Stimulates Proteolytic Liberation of the β-Amyloid Precursor Protein Intracellular Domain." Journal of Biological Chemistry 282, no. 46 (September 11, 2007): 33313–25. http://dx.doi.org/10.1074/jbc.m706024200.

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The β-amyloid precursor protein (APP)-binding protein Fe65 is involved in APP nuclear signaling and several steps in APP proteolytic processing. In this study, we show that Fe65 stimulates γ-secretase-mediated liberation of the APP intracellular domain (AICD). The mechanism of Fe65-mediated stimulation of AICD formation appears to be through enhanced production of the carboxyl-terminal fragment substrates of γ-secretase and direct stimulation of processing by γ-secretase. The stimulatory capacity of Fe65 is isoform-dependent, as the non-neuronal and a2 isoforms promote APP processing more effectively than the exon 9 inclusive neuronal form of Fe65. Intriguingly, Fe65 stimulation of AICD production appears to be inversely related to pathogenic β-amyloid production as the Fe65 isoforms profoundly stimulate AICD production and simultaneously decrease Aβ42 production. Despite the capacity of Fe65 to stimulate γ-secretase-mediated APP proteolysis, it does not rescue the loss of proteolytic function associated with the presenilin-1 familial Alzheimer disease mutations. These data suggest that Fe65 regulation of APP proteolysis may be integrally associated with its nuclear signaling function, as all antecedent proteolytic steps prior to release of Fe65 from the membrane are fostered by the APP-Fe65 interaction.

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Lee, Sangjoon, Tae Kyoo Kim, Ji Eun Choi, Hye-Sun Kim, and Heh-In Im. "Striatal ZBTB16 Is Associated With Cognitive Deficits in Alzheimer Disease Mice." International Neurourology Journal 26, Suppl 2 (November 30, 2022): S106–116. http://dx.doi.org/10.5213/inj.2244254.127.

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Purpose: In Alzheimer disease (AD), brain regions such as the cortex and the hippocampus show abundant amyloid load which correlates with cognitive function decline. Prior to the significant development of AD pathophysiology, patients report the manifestation of neuropsychiatric symptoms, indicating a functional interplay between basal ganglia structures and hippocampal regions. Zinc finger and BTB domain-containing protein 16 (ZBTB16) is a transcription factor that controls the expression of downstream genes and the involvement of ZBTB16 in the striatum undergoing pathological aging in AD and the resulting behavioral phenotypes has not yet been explored.Methods: To study molecular alterations in AD pathogenesis, we analyzed the brain from amyloid precursor protein (APP)/ presenilin 1 (PS1) transgenic mice. The molecular changes in the striatal region of the brain were analyzed via the immunoblotting, and the quantitative RNA sequencing. The cognitive impairments of APP/PS1 mice were assessed via 3 behavioral tests: 3-chamber test, Y-maze test, and noble object recognition test. And multielectrode array experiments for the analysis of the neuronal activity of the striatum in APP/PS1 mice was performed.Results: We found that the alteration in ZBTB16 levels that occurred in the early ages of the pathologically aging striatum coalesces with the disruption of transcriptional dysregulation while causing social memory deficits, anxiety-like behavior. The early ZBTB16 knockdown treatment in the striatum of APP/PS1 mice rescued cognition that continued into later age.Conclusions: This study demonstrates that perturbation of transcriptional regulation of ZBTB16 during pathological aging may influence cognitive impairments and reveals a potent approach to targeting the transcriptional regulation of the striatum for the treatment of AD.

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Bandyopadhyay, Sanghamitra, Jake Ni, Amy Ruggiero, Karen Walshe, Mark S. Rogers, Naibedya Chattopadhyay, Marcie A. Glicksman, and Jack T. Rogers. "A High-Throughput Drug Screen Targeted to the 5'Untranslated Region of Alzheimer Amyloid Precursor Protein mRNA." Journal of Biomolecular Screening 11, no. 5 (April 28, 2006): 469–80. http://dx.doi.org/10.1177/1087057106287271.

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The authors employed a novel approach to identify therapeutics effective in Alzheimer disease (AD). The 5'untranslated region (5'UTR) of the mRNA of AD amyloid precursor protein (APP) is a significant regulator of the levels of the APP holoprotein and amyloid beta (Aβ) peptide in the central nervous system. The authors generated stable neuroblastoma SH-SY5Y transfectants that express luciferase under the translational control of the 146-nucleotide APP mRNA 5'UTR and green fluorescent protein (GFP) driven by a viral internal ribosomal entry site. Using a high-throughput screen (HTS), they screened for the effect of 110,000 compounds obtained from the library of the Laboratory for Drug Discovery on Neurodegeneration (LDDN) on the APP mRNA 5'UTR-controlled translation of the luciferase reporter. This screening yielded several nontoxic specific inhibitors of APP mRNA 5'UTR-driven luciferase that had no effect on the GFP expression in the stable SH-SY5Y transfectants. Moreover, these compounds either did not inhibit or inhibited to a much lower extent the expression of the luciferase reporter regulated by a prion protein (PrP) mRNA 5'UTR, used as an alternative mRNA structure to counterscreen APP mRNA 5'UTR in stably transfected SH-SY5Y cell lines. The hits obtained from this robust, specific, and highly quantitative HTS will be characterized to identify agents that may be developed into useful future therapeutic agents to limit APP translation and Aβ production for AD.

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Lee, Hwa Jeong, Yun Zhang, Chunni Zhu, Karen Duff, and William M. Pardridge. "Imaging Brain Amyloid of Alzheimer Disease in Vivo in Transgenic Mice with an Aβ Peptide Radiopharmaceutical." Journal of Cerebral Blood Flow & Metabolism 22, no. 2 (February 2002): 223–31. http://dx.doi.org/10.1097/00004647-200202000-00010.

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Aβ1–40 is a potential peptide radiopharmaceutical that could be used to image the brain Aβ amyloid of Alzheimer disease in vivo, should this peptide be made transportable through the blood–brain barrier in vivo. The blood–brain barrier transport of [125I]-Aβ1–40 in a transgenic mouse model was enabled by conjugation to the rat 8D3 monoclonal antibody to the mouse transferrin receptor. The Aβ1–40–8D3 conjugate is a bifunctional molecule that binds the blood–brain barrier TfR and undergoes transport into brain and binds the Aβ amyloid plaques of Alzheimer disease. App SW/ Psen1 double-transgenic and littermate control mice were administered either unconjugated Aβ1–40 or the Aβ1–40–8D3 conjugate intravenously, and brain scans were obtained 6 hours later. Immunocytochemical analysis showed abundant Aβ immunoreactive plaques in the brains of the App SW/ Psen1 transgenic mice and there was a selective retention of radioactivity in the brains of these mice at 6 hours after intravenous administration of the conjugate. In contrast, there was no selective sequestration either of the conjugate in control littermate mouse brain or of unconjugated Aβ1–40 in transgenic mouse brain. In conclusion, the results show that it is possible to image the Aβ amyloid burden in the brain in vivo with an amyloid imaging agent, provided the molecule is conjugated to a blood–brain barrier drug-targeting system.

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Grimm, Marcus O. W., Tatjana L. Rothhaar, Sven Grösgen, Verena K. Burg, Benjamin Hundsdörfer, Viola J. Haupenthal, Petra Friess, Stefan Kins, Heike S. Grimm, and Tobias Hartmann. "Trans fatty acids enhance amyloidogenic processing of the Alzheimer amyloid precursor protein (APP)." Journal of Nutritional Biochemistry 23, no. 10 (October 2012): 1214–23. http://dx.doi.org/10.1016/j.jnutbio.2011.06.015.

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Casadesus, Gemma, Kate M. Webber, Craig S. Atwood, Miguel A. Pappolla, George Perry, Richard L. Bowen, and Mark A. Smith. "Luteinizing hormone modulates cognition and amyloid-β deposition in Alzheimer APP transgenic mice." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1762, no. 4 (April 2006): 447–52. http://dx.doi.org/10.1016/j.bbadis.2006.01.008.

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Hiltunen, Mikko, Alice Lu, Anne V. Thomas, Donna M. Romano, Minji Kim, Phill B. Jones, Zhongcong Xie, et al. "Ubiquilin 1 Modulates Amyloid Precursor Protein Trafficking and Aβ Secretion." Journal of Biological Chemistry 281, no. 43 (August 31, 2006): 32240–53. http://dx.doi.org/10.1074/jbc.m603106200.

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Ubiquilin 1 (UBQLN1) is a ubiquitin-like protein, which has been shown to play a central role in regulating the proteasomal degradation of various proteins, including the presenilins. We recently reported that DNA variants in UBQLN1 increase the risk for Alzheimer disease, by influencing expression of this gene in brain. Here we present the first assessment of the effects of UBQLN1 on the metabolism of the amyloid precursor protein (APP). For this purpose, we employed RNA interference to down-regulate UBQLN1 in a variety of neuronal and non-neuronal cell lines. We demonstrate that down-regulation of UBQLN1 accelerates the maturation and intracellular trafficking of APP, while not interfering with α-, β-, or γ-secretase levels or activity. UBQLN1 knockdown increased the ratio of APP mature/immature, increased levels of full-length APP on the cell surface, and enhanced the secretion of sAPP (α- and β-forms). Moreover, UBQLN1 knockdown increased levels of secreted Aβ40 and Aβ42. Finally, employing a fluorescence resonance energy transfer-based assay, we show that UBQLN1 and APP come into close proximity in intact cells, independently of the presence of the presenilins. Collectively, our findings suggest that UBQLN1 may normally serve as a cytoplasmic “gatekeeper” that may control APP trafficking from intracellular compartments to the cell surface. These findings suggest that changes in UBQLN1 steady-state levels affect APP trafficking and processing, thereby influencing the generation of Aβ.

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Levites, Yona, Karen Jansen, Carolina Ceballos, and Todd E. Golde. "P2-303: Anti-amyloid single chain fragments as a tool to target Abeta deposition in APP mouse models." Alzheimer's & Dementia 4 (July 2008): T461. http://dx.doi.org/10.1016/j.jalz.2008.05.1380.

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Mori, Takashi, Naoki Koyama, Tomotaka Yokoo, Tatsuya Segawa, Masahiro Maeda, Darrell Sawmiller, Jun Tan, and Terrence Town. "Gallic acid is a dual α/β-secretase modulator that reverses cognitive impairment and remediates pathology in Alzheimer mice." Journal of Biological Chemistry 295, no. 48 (September 10, 2020): 16251–66. http://dx.doi.org/10.1074/jbc.ra119.012330.

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Several plant-derived compounds have demonstrated efficacy in pre-clinical Alzheimer's disease (AD) rodent models. Each of these compounds share a gallic acid (GA) moiety, and initial assays on this isolated molecule indicated that it might be responsible for the therapeutic benefits observed. To test this hypothesis in a more physiologically relevant setting, we investigated the effect of GA in the mutant human amyloid β-protein precursor/presenilin 1 (APP/PS1) transgenic AD mouse model. Beginning at 12 months, we orally administered GA (20 mg/kg) or vehicle once daily for 6 months to APP/PS1 mice that have accelerated Alzheimer-like pathology. At 18 months of age, GA therapy reversed impaired learning and memory as compared with vehicle, and did not alter behavior in nontransgenic littermates. GA-treated APP/PS1 mice had mitigated cerebral amyloidosis, including brain parenchymal and cerebral vascular β-amyloid deposits, and decreased cerebral amyloid β-proteins. Beneficial effects co-occurred with reduced amyloidogenic and elevated nonamyloidogenic APP processing. Furthermore, brain inflammation, gliosis, and oxidative stress were alleviated. We show that GA simultaneously elevates α- and reduces β-secretase activity, inhibits neuroinflammation, and stabilizes brain oxidative stress in a pre-clinical mouse model of AD. We further demonstrate that GA increases abundance of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10, Adam10) proprotein convertase furin and activates ADAM10, directly inhibits β-site APP cleaving enzyme 1 (BACE1, Bace1) activity but does not alter Adam10 or Bace1 transcription. Thus, our data reveal novel post-translational mechanisms for GA. We suggest further examination of GA supplementation in humans will shed light on the exciting therapeutic potential of this molecule.

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Cirrito, John R., Clare E. Wallace, Ping Yan, Todd A. Davis, Woodrow D. Gardiner, Brookelyn M. Doherty, Diana King, Carla M. Yuede, Jin-Moo Lee, and Yvette I. Sheline. "Effect of escitalopram on Aβ levels and plaque load in an Alzheimer mouse model." Neurology 95, no. 19 (September 10, 2020): e2666-e2674. http://dx.doi.org/10.1212/wnl.0000000000010733.

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BackgroundSeveral neurotransmitter receptors activate signaling pathways that alter processing of the amyloid precursor protein (APP) into β-amyloid (Aβ). Serotonin signaling through a subset of serotonin receptors suppresses Aβ generation. We proposed that escitalopram, the most specific selective serotonin reuptake inhibitor (SSRI) that inhibits the serotonin transporter SERT, would suppress Aβ levels in mice.ObjectivesWe hypothesized that acute treatment with escitalopram would reduce Aβ generation, which would be reflected chronically with a significant reduction in Aβ plaque load.MethodsWe performed in vivo microdialysis and in vivo 2-photon imaging to assess changes in brain interstitial fluid (ISF) Aβ and Aβ plaque size over time, respectively, in the APP/presenilin 1 mouse model of Alzheimer disease treated with vehicle or escitalopram. We also chronically treated mice with escitalopram to determine the effect on plaques histologically.ResultsEscitalopram acutely reduced ISF Aβ by 25% by increasing α-secretase cleavage of APP. Chronic administration of escitalopram significantly reduced plaque load by 28% and 34% at 2.5 and 5 mg/d, respectively. Escitalopram at 5 mg/kg did not remove existing plaques, but completely arrested individual plaque growth over time.ConclusionsEscitalopram significantly reduced Aβ in mice, similar to previous findings in humans treated with acute dosing of an SSRI.

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Stojanovic, Filip, Mariam Taktek, Nam Huan Khieu, Junzhou Huang, Susan Jiang, Kerry Rennie, Balu Chakravarthy, Will J. Costain, and Miroslava Cuperlovic-Culf. "NMR analysis of the correlation of metabolic changes in blood and cerebrospinal fluid in Alzheimer model male and female mice." PLOS ONE 16, no. 5 (May 10, 2021): e0250568. http://dx.doi.org/10.1371/journal.pone.0250568.

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The development of effective therapies as well as early, molecular diagnosis of Alzheimer’s disease is impeded by the lack of understanding of the underlying pathological mechanisms. Metabolomics studies of body fluids as well as brain tissues have shown major changes in metabolic profiles of Alzheimer’s patients. However, with analysis performed at the late stages of the disease it is not possible to distinguish causes and consequence. The mouse model APP/PS1 expresses a mutant amyloid precursor protein resulting in early Amyloid β (Aβ) accumulation as well as many resulting physiological changes including changes in metabolic profile and metabolism. Analysis of metabolic profile of cerebrospinal fluid (CSF) and blood of APP/PS1 mouse model can provide information about metabolic changes in these body fluids caused by Aβ accumulation. Using our novel method for analysis of correlation and mathematical ranking of significant correlations between metabolites in CSF and blood, we have explored changes in metabolite correlation and connectedness in APP/PS1 and wild type mice. Metabolites concentration and correlation changes in CSF, blood and across the blood brain barrier determined in this work are affected by the production of amyloid plaque. Metabolite changes observed in the APP/PS1 mouse model are the response to the mutation causing plaque formation, not the cause for the plaque suggesting that they are less relevant in the context of early treatment and prevention then the metabolic changes observed only in humans.

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Rademakers, Rosa, Marc Cruts, and Christine Van Broeckhoven. "Genetics of Early-Onset Alzheimer Dementia." Scientific World JOURNAL 3 (2003): 497–519. http://dx.doi.org/10.1100/tsw.2003.39.

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Alzheimer�s dementia (AD) is the most common degenerative disorder of the central nervous system. Although the onset of dementia is above 65 years of age in the majority of the patients (late-onset AD, LOAD), a small subgroup of patients develops AD before 65 years of age (early-onset AD, EOAD). To date 3 genes responsible for EOAD have been identified: the amyloid precursor protein gene (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). PSEN1 is the most frequently mutated EOAD gene with a mutation frequency of 18 to 50% in autosomal dominant EOAD. In addition, the e4 allele of the gene encoding apolipoprotein E (APOE) was identified as a risk factor for both LOAD and EOAD. Many studies reported other susceptibility genes, but the APOE?4 alelle has been the only risk factor that was consistently replicated in all AD populations. Extensive cell biology research in the past ten years led to the hypothesis that the 4 EOAD genes lead to AD through a common biological pathway resulting in abnormal APP processing by subtle different mechanisms. Now, transgenic mice are produced to study the influence of EOAD mutations in vivo, eventually leading to the development of novel therapeutic strategies.

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Walls, Ken Carlson, Pinar Coskun, Jose Luis Gallegos-Perez, Nineli Zadourian, Kristine Freude, Suhail Rasool, Mathew Blurton-Jones, Kim Nicholas Green, and Frank Michael LaFerla. "Swedish Alzheimer Mutation Induces Mitochondrial Dysfunction Mediated by HSP60 Mislocalization of Amyloid Precursor Protein (APP) and Beta-Amyloid." Journal of Biological Chemistry 287, no. 36 (June 29, 2012): 30317–27. http://dx.doi.org/10.1074/jbc.m112.365890.

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Freude, Kristine K., Mahmud Penjwini, Joy L. Davis, Frank M. LaFerla, and Mathew Blurton-Jones. "Soluble Amyloid Precursor Protein Induces Rapid Neural Differentiation of Human Embryonic Stem Cells." Journal of Biological Chemistry 286, no. 27 (May 23, 2011): 24264–74. http://dx.doi.org/10.1074/jbc.m111.227421.

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Human embryonic stem cells (hESCs) offer tremendous potential for not only treating neurological disorders but also for their ability to serve as vital reagents to model and investigate human disease. To further our understanding of a key protein involved in Alzheimer disease pathogenesis, we stably overexpressed amyloid precursor protein (APP) in hESCs. Remarkably, we found that APP overexpression in hESCs caused a rapid and robust differentiation of pluripotent stem cells toward a neural fate. Despite maintenance in standard hESC media, up to 80% of cells expressed the neural stem cell marker nestin, and 65% exhibited the more mature neural marker β-3 tubulin within just 5 days of passaging. To elucidate the mechanism underlying the effects of APP on neural differentiation, we examined the proteolysis of APP and performed both gain of function and loss of function experiments. Taken together, our results demonstrate that the N-terminal secreted soluble forms of APP (in particular sAPPβ) robustly drive neural differentiation of hESCs. Our findings not only reveal a novel and intriguing role for APP in neural lineage commitment but also identify a straightforward and rapid approach to generate large numbers of neurons from human embryonic stem cells. These novel APP-hESC lines represent a valuable tool to investigate the potential role of APP in development and neurodegeneration and allow for insights into physiological functions of this protein.

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Bécot, Anaïs, Charlotte Volgers, and Guillaume van Niel. "Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation." Biomedicines 8, no. 8 (August 4, 2020): 272. http://dx.doi.org/10.3390/biomedicines8080272.

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In Alzheimer′s disease (AD), endolysosomal dysfunctions are amongst the earliest cellular features to appear. Each organelle of the endolysosomal system, from the multivesicular body (MVB) to the lysosome, contributes to the homeostasis of amyloid precursor protein (APP) cleavage products including β-amyloid (Aβ) peptides. Hence, this review will attempt to disentangle how changes in the endolysosomal system cumulate to the generation of toxic amyloid species and hamper their degradation. We highlight that the formation of MVBs and the generation of amyloid species are closely linked and describe how the molecular machineries acting at MVBs determine the generation and sorting of APP cleavage products towards their degradation or release in association with exosomes. In particular, we will focus on AD-related distortions of the endolysomal system that divert it from its degradative function to favour the release of exosomes and associated amyloid species. We propose here that such an imbalance transposed at the brain scale poses a novel concept of transmissible endosomal intoxication (TEI). This TEI would initiate a self-perpetuating transmission of endosomal dysfunction between cells that would support the propagation of amyloid species in neurodegenerative diseases.

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Munter, Lisa-Marie, Anne Botev, Luise Richter, Peter W. Hildebrand, Veit Althoff, Christoph Weise, Daniela Kaden, and Gerd Multhaup. "Aberrant Amyloid Precursor Protein (APP) Processing in Hereditary Forms of Alzheimer Disease Caused by APP Familial Alzheimer Disease Mutations Can Be Rescued by Mutations in the APP GxxxG Motif." Journal of Biological Chemistry 285, no. 28 (May 7, 2010): 21636–43. http://dx.doi.org/10.1074/jbc.m109.088005.

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Rovelet-Lecrux, Anne, Didier Hannequin, Gregory Raux, Nathalie Le Meur, Annie Laquerrière, Anne Vital, Cécile Dumanchin, et al. "APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy." Nature Genetics 38, no. 1 (December 20, 2005): 24–26. http://dx.doi.org/10.1038/ng1718.

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Pavisic, Ivanna M., Jennifer M. Nicholas, Antoinette O'Connor, Helen Rice, Kirsty Lu, Nick C. Fox, and Natalie S. Ryan. "Disease duration in autosomal dominant familial Alzheimer disease." Neurology Genetics 6, no. 5 (August 18, 2020): e507. http://dx.doi.org/10.1212/nxg.0000000000000507.

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ObjectiveTo use survival modeling to estimate disease duration in autosomal dominant familial Alzheimer disease (ADAD) and ascertain whether factors influencing age at onset also affect survival.MethodsSymptomatic mutation carriers (201 presenilin 1 [PSEN1] and 55 amyloid precursor protein [APP]) from ADAD families referred to the Dementia Research Centre, between 1987 and 2019, were included. Survival was assessed with respect to age at onset, year of birth, APOE ε4 status, cognitive presentation, and sex using multilevel mixed-effects Weibull survival models. The contribution of mutation and family to variance in age at onset and duration was also assessed.ResultsEstimated mean survival was 11.6 (10.4–12.9) years and was similar for APP and PSEN1 mutations. Sixty-seven percent of the variance in age at onset was explained by mutation and 72% by mutation and family together. In contrast, only 6% of the variance in disease duration was explained by mutation specificity and 18% by family membership. Irrespective of gene, survival appeared longer for successive generations and in individuals with atypical presentations. Older age at onset was associated with longer duration within PSEN1 and shorter duration within APP mutation carriers. No differences in survival time were found between sexes or between mutations located before or beyond codon 200 within PSEN1.ConclusionsSurvival is influenced by mutation to a much lesser extent than age at onset. Survival time has increased over time and is longer in atypical presentations. These insights may inform the interpretation of disease-modifying therapy trials in ADAD.

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Irfannudin, Irfannudin. "Biomolecular Characteristics of Amyloid Precursor Protein Mutations As Causes of Alzheimer's Disease Analyzed Through Bioinformatics Media." SRIWIJAYA JOURNAL OF MEDICINE 1, no. 1 (January 31, 2018): 61–73. http://dx.doi.org/10.32539/sjm.v1i1.9.

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Methods of biomolecular analysis on protein through bioinformatics media has been growing rapidly. This report is intended to describe the results of biomolecular amyloid precursor protein (APP) analysis and the characteristic change of APP mutations causing cognitive degeneration disorder through bioinformatics media and search to reliable biomolecular sites. APP is a transmembrane protein that is widely present in neuronal tissue. APP plays an important role for the formation of neuronal cells. The APP gene is located on the 21st chromosome that has 290,586 base pairs (bp) of 20 exons and 19 introns. In the form of a protein, APP consists of 770 amino acids with major expressions located on the cell surface. Mutation of APP genes is believed to play a role in the incidence of Alzheimer's disease. One of the mutations studied in this paper is the mutation of Alanin to Glysin at the position of the 692 amino acid (APP mutant A692G). This mutation affects the impairment of cerebral amyloid angiopathy belonging to the Alzheimer Disease Familial-1 group.These mutations do not cause changes in predictions of secondary structures and only cause slight changes in molecular weight, amino acid composition, atomic composition, aliphatic index, hydroplasticity and stability index. APP A692G mutation does not alter topology, hydrophobicity, cutting prediction and protein location prediction. Mutation also removes only the side chains at the position of the mutated amino acids.

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Xie, Zhongcong, Yuanlin Dong, Uta Maeda, Weiming Xia, and Rudolph E. Tanzi. "RNA Interference Silencing of the Adaptor Molecules ShcC and Fe65 Differentially Affect Amyloid Precursor Protein Processing and Aβ Generation." Journal of Biological Chemistry 282, no. 7 (December 14, 2006): 4318–25. http://dx.doi.org/10.1074/jbc.m609293200.

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The amyloid precursor protein (APP) and its pathogenic by-product amyloid-β protein (Aβ) play central roles in Alzheimer disease (AD) neuropathogenesis. APP can be cleaved by β-secretase (BACE) and α-secretase to produce APP-C99 and APP-C83. These C-terminal fragments can then be cleaved by γ-secretase to produce Aβ and p3, respectively. p3 has been reported to promote apoptosis, and Aβ is the key component of senile plaques in AD brain. APP adaptor proteins with phosphotyrosine-binding domains, including ShcA (SHC1), ShcC (SHC3), and Fe65 (APBB1), can bind to and interact with the conserved YENPTY motif in the APP-C terminus. Here we have described for the first time the effects of RNA interference (RNAi) silencing of ShcA, ShcC, and Fe65 expression on APP processing and Aβ production. RNAi silencing of ShcC led to reductions in the levels of APP-C-terminal fragments (APP-CTFs) and Aβ in H4 human neuroglioma cells stably overexpressing full-length APP (H4-FL-APP cells) but not in those expressing APP-C99 (H4-APP-C99 cells). RNAi silencing of ShcC also led to reductions in BACE levels in H4-FL-APP cells. In contrast, RNAi silencing of the homologue ShcA had no effect on APP processing or Aβ levels. RNAi silencing of Fe65 increased APP-CTF levels, although also decreasing Aβ levels in H4-FL-APP cells. These findings suggest that pharmacologically blocking interaction of APP with ShcC and Fe65 may provide novel therapeutic strategies against AD.

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Journal articles on the topic 'AMYLOID, APP, ABETA, ALZHEIMER'

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