Journal articles: 'Tau protein deposits'

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Andrés-Benito, Pol, Margarita Carmona, Mónica Jordán, Joaquín Fernández-Irigoyen, Enrique Santamaría, José Antoni del Rio, and Isidro Ferrer. "Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD Inoculum." International Journal of Molecular Sciences 23, no. 2 (January 10, 2022): 718. http://dx.doi.org/10.3390/ijms23020718.

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Several studies have demonstrated the different characteristics of tau seeding and spreading following intracerebral inoculation in murine models of tau-enriched fractions of brain homogenates from AD and other tauopathies. The present study is centered on the importance of host tau in tau seeding and the molecular changes associated with the transformation of host tau into abnormal tau. The brains of three adult murine genotypes expressing different forms of tau—WT (murine 4Rtau), hTau (homozygous transgenic mice knock-out for murine tau protein and heterozygous expressing human forms of 3Rtau and 4Rtau proteins), and mtWT (homozygous transgenic mice knock-out for murine tau protein)—were analyzed following unilateral hippocampal inoculation of sarkosyl-insoluble tau fractions from the same AD and control cases. The present study reveals that (a) host tau is mandatory for tau seeding and spreading following tau inoculation from sarkosyl-insoluble fractions obtained from AD brains; (b) tau seeding does not occur following intracerebral inoculation of sarkosyl-insoluble fractions from controls; (c) tau seeding and spreading are characterized by variable genotype-dependent tau phosphorylation and tau nitration, MAP2 phosphorylation, and variable activation of kinases that co-localize with abnormal tau deposits; (d) transformation of host tau into abnormal tau is an active process associated with the activation of specific kinases; (e) tau seeding is accompanied by modifications in tau splicing, resulting in the expression of new 3Rtau and 4Rtau isoforms, thus indicating that inoculated tau seeds have the capacity to model exon 10 splicing of the host mapt or MAPT with a genotype-dependent pattern; (e) selective regional and cellular vulnerabilities, and different molecular compositions of the deposits, are dependent on the host tau of mice injected with identical AD tau inocula.

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Ukmar-Godec, T., P. Fang, A. Ibáñez de Opakua, F. Henneberg, A. Godec, K. T. Pan, M. S. Cima-Omori, et al. "Proteasomal degradation of the intrinsically disordered protein tau at single-residue resolution." Science Advances 6, no. 30 (July 2020): eaba3916. http://dx.doi.org/10.1126/sciadv.aba3916.

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Intrinsically disordered proteins (IDPs) can be degraded in a ubiquitin-independent process by the 20S proteasome. Decline in 20S activity characterizes neurodegenerative diseases. Here, we examine 20S degradation of IDP tau, a protein that aggregates into insoluble deposits in Alzheimer’s disease. We show that cleavage of tau by the 20S proteasome is most efficient within the aggregation-prone repeat region of tau and generates both short, aggregation-deficient peptides and two long fragments containing residues 1 to 251 and 1 to 218. Phosphorylation of tau by the non-proline–directed Ca2+/calmodulin-dependent protein kinase II inhibits degradation by the 20S proteasome. Phosphorylation of tau by GSK3β, a major proline-directed tau kinase, modulates tau degradation kinetics in a residue-specific manner. The study provides detailed insights into the degradation products of tau generated by the 20S proteasome, the residue specificity of degradation, single-residue degradation kinetics, and their regulation by posttranslational modification.

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Oliveira, Francine Hehn de, Edson Rodrigues Neto, Mariana Kumaira Fonseca, André Silvestre Reitz da Costa, Marcio Aloisio Bezerra Cavalcanti Rockenbach, Renata dos Santos Padilha, Liana Lisboa Fernandez, and Arlete Hilbig. "Neurodegenerative changes in the brainstem and olfactory bulb in people older than 50 years old: a descriptive study." Arquivos de Neuro-Psiquiatria 73, no. 7 (July 2015): 569–77. http://dx.doi.org/10.1590/0004-282x20150066.

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With the increase in life expectancy in Brazil, concerns have grown about the most prevalent diseases in elderly people. Among these diseases are neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. Protein deposits related to the development of these diseases can pre-date the symptomatic phases by years. The tau protein is particularly interesting: it might be found in the brainstem and olfactory bulb long before it reaches the limbic cortex, at which point symptoms occur. Of the 14 brains collected in this study, the tau protein was found in the brainstems of 10 (71.42%) and in olfactory bulbs of 3 out 11. Of the 7 individuals who had a final diagnosis of Alzheimer’s disease (AD), 6 presented tau deposits in some region of the brainstem. Our data support the idea of the presence of tau protein in the brainstem and olfactory bulb in the earliest stages of AD.

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Kovacs, G. G., S. Klotz, P. Fischer, M. Hinterberger, G. Ricken, S. Hönigschnabl, and E. Gelpi. "Complex Protein Astrogliopathy in an Octogenarian." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 48, s2 (July 2021): S10. http://dx.doi.org/10.1017/cjn.2021.169.

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Combination of multiple neurodegenerative proteinopathies is frequent in the elderly. We report the case of an octogenarian who attempted suicide and deceased after hospital admission. Anatomical mapping was performed in several cortical and subcortical brain regions using antibodies against phospho-tau, 4R tau, 3R tau, phospho-TDP-43, ubiquitin, α-synuclein, Aβ and p62. Unexpectedly, histopathologic examination showed prominent subpial, subependymal, grey and white matter, and perivascular aging-related tau astrogliopathy (ARTAG) affecting cortical and subcortical brain regions. This pathology was associated with intermediate Alzheimer’s disease neuropathologic change, cerebral amyloid angiopathy, Lewy-body-type and astroglial synuclein proteinopathy and a multiple system TDP-43 proteinopathy involving also the astroglia. This unusual case of extensive and widespread ARTAG with a complex multiproteinopathy may represent an independent disease entity in the elderly with tau astrogliopathy as the leading force.Learning ObjectiveRecognize astroglial protein deposits in neurodegeneration

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Goedert, M., R. Jakes, R. A. Crowther, M. Hasegawa, M. J. Smith, and M. G. Spillantini. "Intraneuronal filamentous tau protein and α-synuclein deposits in neurodegenerative diseases." Biochemical Society Transactions 26, no. 3 (August 1, 1998): 463–71. http://dx.doi.org/10.1042/bst0260463.

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Piccardo, Pedro, Declan King, Deborah Brown, and Rona M. Barron. "Variable tau accumulation in murine models with abnormal prion protein deposits." Journal of the Neurological Sciences 383 (December 2017): 142–50. http://dx.doi.org/10.1016/j.jns.2017.10.040.

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Rodrigues Neto, Edson, Mariana K. Fonseca, Álvaro C. B. Guedes, Francine H. Oliveira, Arlete Hilbig, and Liana Lisboa Fernandez. "Neuropathological findings in entorhinal cortex of subjects aged 50 years or older and their correlation with dementia in a sample from Southern Brazil." Dementia & Neuropsychologia 11, no. 1 (March 2017): 24–31. http://dx.doi.org/10.1590/1980-57642016dn11-010005.

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ABSTRACT Introduction: The aims of this study were to survey neurodegenerative changes detected by abnormal protein deposits in the Entorhinal Cortex (EC) of subjects aged 50 years or older and to correlate these findings with suspected dementia, as detected by the IQCODE (Informant Questionnaire on Cognitive Decline in the Elderly) . Methods: Fourteen brains were submitted to the immunohistochemistry technique for different proteins (beta-amyloid, tau, -synuclein and phospho-TDP-43) and data obtained compared with IQCODE scores. Results: Fifty-seven percent of the individuals exhibited IQCODE results compatible with dementia, being classified into the demented group (DG): 87.5% of patients had neuropathological findings corresponding to Alzheimer's-like brain pathology (ALBP). Of the patients in the non-demented group (NDG), 16.7% met neuropathological criteria for ALBP. All individuals in the DG showed deposits of more than one kind of protein in the EC. The most common association was hyperphosphorylated tau and beta-amyloid protein (87.5%). Discussion: Most individuals with dementia had neuropathological findings of ALBP, as did one individual with no signs of dementia, characterizing a preclinical stage. The results of this study suggest that deposits of a single type of anomalous protein are normal findings in an aging brain, while more than one kind of protein or the combined presence of anomalous protein deposits indicate the presence of dementia.

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Kasho, Kazutoshi, Lukas Krasauskas, Vytautas Smirnovas, Gorazd Stojkovič, Ludmilla A. Morozova-Roche, and Sjoerd Wanrooij. "Human Polymerase δ-Interacting Protein 2 (PolDIP2) Inhibits the Formation of Human Tau Oligomers and Fibrils." International Journal of Molecular Sciences 22, no. 11 (May 28, 2021): 5768. http://dx.doi.org/10.3390/ijms22115768.

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A central characteristic of Alzheimer’s disease (AD) and other tauopathies is the accumulation of aggregated and misfolded Tau deposits in the brain. Tau-targeting therapies for AD have been unsuccessful in patients to date. Here we show that human polymerase δ-interacting protein 2 (PolDIP2) interacts with Tau. With a set of complementary methods, including thioflavin-T-based aggregation kinetic assays, Tau oligomer-specific dot-blot analysis, and single oligomer/fibril analysis by atomic force microscopy, we demonstrate that PolDIP2 inhibits Tau aggregation and amyloid fibril growth in vitro. The identification of PolDIP2 as a potential regulator of cellular Tau aggregation should be considered for future Tau-targeting therapeutics.

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Maj, Magdalena, Wolfgang Gartner, Aysegul Ilhan, Dashurie Neziri, Johannes Attems, and Ludwig Wagner. "Expression of TAU in insulin-secreting cells and its interaction with the calcium-binding protein secretagogin." Journal of Endocrinology 205, no. 1 (January 8, 2010): 25–36. http://dx.doi.org/10.1677/joe-09-0341.

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Tauopathies have been associated with Alzheimer's disease (AD), which frequently manifests together with diabetes mellitus type 2. Calcium-binding proteins such as the recently identified secretagogin (SCGN) might exert protective effects. As pancreatic β-cells and neurons share common electrophysiological properties, we investigated the appearance of TAU (listed as MAPT in the HUGO and MGI Databases) protein at the islets of Langerhans and β-cell-derived cell lines which highly express the neuroendocrine-specific protein SCGN. Six predominant TAU isoforms could be identified by immunoblotting, which formed TAU deposits detectable by immunofluorescence and sarkosyl-insoluble pellets. Using GST–SCGN pull-down assays, a calcium-dependent SCGN–TAU interaction was found. In this line, sucrose density gradient fractionation and differential ultracentrifugation studies of TAU and SCGN revealed co-appearance of both proteins. Co-localization of TAU and SCGN within insulinoma cells and islets of Langerhans mainly restricted to insulin-positive β-cells was demonstrated by confocal microscopy. Motivated by these findings, we looked if SCGN overexpression could exert protective function on Rin-5F cells, which showed differences in TAU levels. Testing the vulnerability of Rin-5F clones by MTT assay, we revealed that high TAU levels going along with highest TAU aggregates could not be antagonized by high levels of SCGN protein. Our findings demonstrated for the first time the association of TAU and the calcium-binding protein SCGN and support earlier results implicating that β-cells might represent an extra cerebral site of tauopathy.

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Kundra, Rishika, Prajwal Ciryam, Richard I. Morimoto, Christopher M. Dobson, and Michele Vendruscolo. "Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease." Proceedings of the National Academy of Sciences 114, no. 28 (June 26, 2017): E5703—E5711. http://dx.doi.org/10.1073/pnas.1618417114.

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Alzheimer’s disease is the most common cause of dementia. A hallmark of this disease is the presence of aberrant deposits containing by the Aβ peptide (amyloid plaques) and the tau protein (neurofibrillary tangles) in the brains of affected individuals. Increasing evidence suggests that the formation of these deposits is closely associated with the age-related dysregulation of a large set of highly expressed and aggregation-prone proteins, which make up a metastable subproteome. To understand in more detail the origins of such dysregulation, we identify specific components of the protein homeostasis system associated with these metastable proteins by using a gene coexpression analysis. Our results reveal the particular importance of the protein trafficking and clearance mechanisms, including specific branches of the endosomal–lysosomal and ubiquitin–proteasome systems, in maintaining the homeostasis of the metastable subproteome associated with Alzheimer’s disease.

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Hallinan, Grace I., Md Rejaul Hoq, Manali Ghosh, Frank S. Vago, Anllely Fernandez, Holly J. Garringer, Ruben Vidal, Wen Jiang, and Bernardino Ghetti. "Structure of Tau filaments in Prion protein amyloidoses." Acta Neuropathologica 142, no. 2 (June 14, 2021): 227–41. http://dx.doi.org/10.1007/s00401-021-02336-w.

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AbstractIn human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) with a nonsense mutation in the PRNP gene that leads to early termination of translation of PrP (Q160Ter or Q160X), and Gerstmann–Sträussler–Scheinker (GSS) disease, with a missense mutation in the PRNP gene that leads to an amino acid substitution at residue 198 (F198S) of PrP. The clinical and neuropathologic phenotypes associated with these two mutations in PRNP are different; however, the neuropathologic analyses of these two genetic variants have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA (Q160X) and GSS (F198S) are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA (Q160X), Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS (F198S), only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA (Q160X) and GSS (F198S) brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA (Q160X) and GSS (F198S) are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of extracellular amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.

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Goedert, Michel, and Maria Grazia Spillantini. "Tau gene mutations and neurodegeneration." Biochemical Society Symposia 67 (February 1, 2001): 59–71. http://dx.doi.org/10.1042/bss0670059.

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Abundant neurofibrillary lesions made of the microtubule-associated protein tau constitute a defining neuropathological characteristic of Alzheimer's disease. Filamentous tau protein deposits are also the defining neuropathological characteristic of other neurodegenerative diseases, many of which are frontotemporal dementias or movement disorders, such as Pick's disease, progressive supranuclear palsy and corticobasal degeneration. It is well established that the distribution of tau pathology correlates with the presence of symptoms of disease. However, until recently, there was no genetic evidence linking dysfunction of tau protein to neurodegeneration and dementia. This has now changed with the discovery of close to 20 mutations in the tau gene in frontotemporal dementia with Parkinsonism linked to chromosome 17. All cases with tau mutations examined to date have shown an abundant filamentous tau pathology in brain cells. Pathological heterogeneity is determined to a large extent by the location of mutations in tau. Known mutations are either coding region or intronic mutations located close to the splice-donor site of the intron downstream of exon 10. Most coding region mutations produce a reduced ability of tau to interact with microtubules. Several of these mutations also promote sulphated glycosaminoglycan-induced assembly of tau into filaments. Intronic mutations and some coding region mutations produce increased splicing in of exon 10, resulting in an overexpression of four-repeat tau isoforms. Thus a normal ratio of three-repeat to four-repeat tau isoforms is essential for preventing the development of tau pathology. The new work has shown that dysfunction of tau protein can cause neurodegeneration and dementia.

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Chang, Joanna K., Allison Leso, Gehad M. Subaiea, Asma Lahouel, Anwar Masoud, Foqia Mushtaq, Reem Deeb, et al. "Tolfenamic Acid: A Modifier of the Tau Protein and its Role in Cognition and Tauopathy." Current Alzheimer Research 15, no. 7 (May 9, 2018): 655–63. http://dx.doi.org/10.2174/1567205015666180119104036.

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Background: Tangles are deposits of hyperphosphorylated tau, which are found in multiple neurodegenerative disorders that are referred to as tauopathies, of which Alzheimer's disease (AD) is the most common. Tauopathies are clinically characterized by dementia and share common cortical lesions composed of aggregates of the protein tau. Objective: In this study, we explored the therapeutic potential of tolfenamic acid (TA), in modifying disease processes in a transgenic animal model that carries the human tau gene (hTau). Methods: Behavioral tests, Western blotting and Immunohistochemical analysis were used to demonstrate the efficacy of TA. Results: Treatment of TA improved improving spatial learning deficits and memory impairments in young and aged hTau mice. Western blot analysis of the hTau protein revealed reductions in total tau as well as in sitespecific hyperphosphorylation of tau in response to TA administration. Immunohistochemical analysis for phosphorylated tau protein revealed reduced staining in the frontal cortex, hippocampus, and striatum in animals treated with TA. Conclusion: TA holds the potential as a disease-modifying agent for the treatment of tauopathies including AD.

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Ferrer, I., M. Barrachina, M. Tolnay, M. J. Rey, N. Vidal, M. Carmona, R. Blanco, and B. Puig. "Phosphorylated Protein Kinases Associated with Neuronal and Glial Tau Deposits in Argyrophilic Grain Disease." Brain Pathology 13, no. 1 (April 5, 2006): 62–78. http://dx.doi.org/10.1111/j.1750-3639.2003.tb00007.x.

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Münch, G., B. Kuhla, H. J. Lüth, T. Arendt, and S. R. Robinson. "Anti-AGEing defences against Alzheimer's disease." Biochemical Society Transactions 31, no. 6 (December 1, 2003): 1397–99. http://dx.doi.org/10.1042/bst0311397.

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Accumulation of insoluble protein deposits and their cross-linking by AGEs (advanced glycation end products) in the brain is a feature of aging and neurodegeneration, especially in AD (Alzheimer's disease). In AD, two types of fibrillar protein aggregates are present: extracellular deposits (plaques) consisting mainly of Aβ (β-amyloid peptide), and intracellular deposits (tangles) composed predominantly of microtubule-associated protein tau. Both plaques and tangles are modified by AGEs, which occurs particularly at lysine and arginine residues. Interaction of a synthetic amyloid plaque (fibrillar Aβ) with microglia leads to a strong pro-inflammatory response, indicating that priming of immune cells with β-amyloid potentiates their response to secondary stimuli such as AGE and cytokines such as interferon-γ. Formation of hyperphosphorylated and cross-linked microtubule-associated protein tau aggregates, especially tau dimers as the first step in tangle formation, can be induced in vitro by the combination of okadaic acid, a PP2A phosphatase inhibitor, and methylglyoxal. These results suggest that excess production of reactive carbonyl compound (‘carbonyl stress’) and subsequent AGE formation can contribute to cross-linking of protein fibrils and to pathological pro-inflammatory signalling, which all contribute to pathological changes and dementia progression in AD. However, the human brain has developed the glyoxalase system, a most effective defence system to scavenge small dicarbonyl compounds such as glyoxal and methylglyoxal. Very importantly, this system needs GSH as a rate-limiting cofactor. Since GSH is limited under conditions of oxidative stress and inflammation, supplementation with antioxidants such as lipoic acid, vitamin E or flavonoids could indirectly strengthen the anti-glycation defence system in AD. In addition, synthetic carbonyl scavengers and anti-inflammatory drugs could also be valuable drugs for the ‘anti-glycation’ treatment of AD.

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Wheeler, Jeanna M., Chris R. Guthrie, and Brian C. Kraemer. "Potential neuroprotective strategies against tauopathy." Biochemical Society Transactions 40, no. 4 (July 20, 2012): 656–60. http://dx.doi.org/10.1042/bst20120017.

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Tauopathies are neurodegenerative diseases, including AD (Alzheimer's disease) and FTLD-T (tau-positive frontotemporal lobar degeneration), with shared pathology presenting as accumulation of detergent-insoluble hyperphosphorylated tau deposits in the central nervous system. The currently available treatments for AD address only some of the symptoms, and do not significantly alter the progression of the disease, namely the development of protein aggregates and loss of functional neurons. The development of effective treatments for various tauopathies will require the identification of common mechanisms of tau neurotoxicity, and pathways that can be modulated to protect against neurodegeneration. Model organisms, such as Caenorhabditis elegans, provide methods for identifying novel genes and pathways that are involved in tau pathology and may be exploited for treatment of various tauopathies. In the present paper, we summarize data regarding characterization of MSUT2 (mammalian suppressor of tau pathology 2), a protein identified in a C. elegans tauopathy model and subsequently shown to modify tau toxicity in mammalian cell culture via the effects on autophagy pathways. MSUT2 represents a potential drug target for prevention of tau-related neurodegeneration.

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Qu, Zhong-Sen, Liang Li, Xiao-Jiang Sun, Yu-Wu Zhao, Jin Zhang, Zhi Geng, Jian-Liang Fu, and Qing-Guo Ren. "Glycogen Synthase Kinase-3 Regulates Production of Amyloid-βPeptides and Tau Phosphorylation in Diabetic Rat Brain." Scientific World Journal 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/878123.

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The pathogenesis of diabetic neurological complications is not fully understood. Diabetes mellitus (DM) and Alzheimer’s disease (AD) are characterized by amyloid deposits. Glycogen synthase kinase-3 (GSK-3) plays an important role in the pathogenesis of AD and DM. Here we tried to investigate the production of amyloid-βpeptides (Aβ) and phosphorylation of microtubule-associated protein tau in DM rats and elucidate the role of GSK-3 and Akt (protein kinase B, PKB) in these processes. Streptozotocin injection-induced DM rats displayed an increased GSK-3 activity, decreased activity and expression of Akt. And Aβ40 and Aβ42 were found overproduced and the microtubule-associated protein tau was hyperphosphorylated in the hippocampus. Furthermore, selective inhibition of GSK-3 by lithium could attenuate the conditions of Aβoverproduction and tau hyperphosphorylation. Taken together, our studies suggest that GSK-3 regulates both the production of Aβand the phosphorylation of tau in rat brain and may therefore contribute to DM caused AD-like neurological defects.

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Piccardo, Pedro, and David M. Asher. "Complex proteinopathies and neurodegeneration: insights from the study of transmissible spongiform encephalopathies." Arquivos de Neuro-Psiquiatria 76, no. 10 (October 2018): 705–12. http://dx.doi.org/10.1590/0004-282x20180111.

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ABSTRACT Protein misfolding diseases are usually associated with deposits of single “key” proteins that somehow drive the pathology; β-amyloid and hyperphosphorylated tau accumulate in Alzheimer's disease, α-synuclein in Parkinson's disease, or abnormal prion protein (PrPTSE) in transmissible spongiform encephalopathies (TSEs or prion diseases). However, in some diseases more than two proteins accumulate in the same brain. These diseases might be considered “complex” proteinopathies. We have studied models of TSEs (to explore deposits of PrPTSE and of “secondary proteins”) infecting different strains and doses of TSE agent, factors that control incubation period, duration of illness and histopathology. Model TSEs allowed us to investigate whether different features of histopathology are independent of PrPTSE or appear as a secondary result of PrPTSE. Better understanding the complex proteinopathies may help to explain the wide spectrum of degenerative diseases and why some overlap clinically and histopathologically. These studies might also improve diagnosis and eventually even suggest new treatments for human neurodegenerative diseases.

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Maté de Gérando, Anastasie, Marie d’Orange, Emma Augustin, Charlène Joséphine, Gwénaelle Aurégan, Mylène Gaudin-Guérif, Martine Guillermier, et al. "Neuronal tau species transfer to astrocytes and induce their loss according to tau aggregation state." Brain 144, no. 4 (April 1, 2021): 1167–82. http://dx.doi.org/10.1093/brain/awab011.

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Abstract Deposits of different abnormal forms of tau in neurons and astrocytes represent key anatomo-pathological features of tauopathies. Although tau protein is highly enriched in neurons and poorly expressed by astrocytes, the origin of astrocytic tau is still elusive. Here, we used innovative gene transfer tools to model tauopathies in adult mouse brains and to investigate the origin of astrocytic tau. We showed in our adeno-associated virus (AAV)-based models and in Thy-Tau22 transgenic mice that astrocytic tau pathology can emerge secondarily to neuronal pathology. By designing an in vivo reporter system, we further demonstrated bidirectional exchanges of tau species between neurons and astrocytes. We then determined the consequences of tau accumulation in astrocytes on their survival in models displaying various status of tau aggregation. Using stereological counting of astrocytes, we report that, as for neurons, soluble tau species are highly toxic to some subpopulations of astrocytes in the hippocampus, whereas the accumulation of tau aggregates does not affect their survival. Thus, astrocytes are not mere bystanders of neuronal pathology. Our results strongly suggest that tau pathology in astrocytes may significantly contribute to clinical symptoms.

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Ashok, Ajay, Neena Singh, Suman Chaudhary, Vindhya Bellamkonda, Alexander E. Kritikos, Aaron S. Wise, Neil Rana, Dallas McDonald, and Rithvik Ayyagari. "Retinal Degeneration and Alzheimer’s Disease: An Evolving Link." International Journal of Molecular Sciences 21, no. 19 (October 2, 2020): 7290. http://dx.doi.org/10.3390/ijms21197290.

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Age-related macular degeneration (AMD) and glaucoma are degenerative conditions of the retina and a significant cause of irreversible blindness in developed countries. Alzheimer’s disease (AD), the most common dementia of the elderly, is often associated with AMD and glaucoma. The cardinal features of AD include extracellular accumulation of amyloid β (Aβ) and intracellular deposits of hyper-phosphorylated tau (p-tau). Neuroinflammation and brain iron dyshomeostasis accompany Aβ and p-tau deposits and, together, lead to progressive neuronal death and dementia. The accumulation of Aβ and iron in drusen, the hallmark of AMD, and Aβ and p-tau in retinal ganglion cells (RGC), the main retinal cell type implicated in glaucoma, and accompanying inflammation suggest overlapping pathology. Visual abnormalities are prominent in AD and are believed to develop before cognitive decline. Some are caused by degeneration of the visual cortex, while others are due to RGC loss or AMD-associated retinal degeneration. Here, we review recent information on Aβ, p-tau, chronic inflammation, and iron dyshomeostasis as common pathogenic mechanisms linking the three degenerative conditions, and iron chelation as a common therapeutic option for these disorders. Additionally discussed is the role of prion protein, infamous for prion disorders, in Aβ-mediated toxicity and, paradoxically, in neuroprotection.

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Jazvinšćak Jembrek, Maja, Patrick R. Hof, and Goran Šimić. "Ceramides in Alzheimer’s Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and AβAccumulation." Oxidative Medicine and Cellular Longevity 2015 (2015): 1–17. http://dx.doi.org/10.1155/2015/346783.

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Alzheimer’s disease (AD), the most common chronic and progressive neurodegenerative disorder, is characterized by extracellular deposits of amyloidβ-peptides (Aβ) and intracellular deposits of hyperphosphorylated tau (phospho-tau) protein. Ceramides, the major molecules of sphingolipid metabolism and lipid second messengers, have been associated with AD progression and pathology via Aβgeneration. Enhanced levels of ceramides directly increase Aβthrough stabilization ofβ-secretase, the key enzyme in the amyloidogenic processing of Aβprecursor protein (APP). As a positive feedback loop, the generated oligomeric and fibrillar Aβinduces a further increase in ceramide levels by activating sphingomyelinases that catalyze the catabolic breakdown of sphingomyelin to ceramide. Evidence also supports important role of ceramides in neuronal apoptosis. Ceramides may initiate a cascade of biochemical alterations, which ultimately leads to neuronal death by diverse mechanisms, including depolarization and permeabilization of mitochondria, increased production of reactive oxygen species (ROS), cytochrome c release, Bcl-2 depletion, and caspase-3 activation, mainly by modulating intracellular signalling, particularly along the pathways related to Akt/PKB kinase and mitogen-activated protein kinases (MAPKs). This review summarizes recent findings related to the role of ceramides in oxidative stress-driven neuronal apoptosis and interplay with Aβin the cascade of events ending in neuronal degeneration.

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Sennik, S., M. Anton, M. Cusimano, and D. G. Munoz. "13. Idiopathic Normal Pressure Hydrocephalus: Pathological changes in cortical biopsies in relation to function and response to treatment." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 42, S2 (August 2015): S5. http://dx.doi.org/10.1017/cjn.2015.261.

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Cortical peri-operative biopsies obtained from 11 idiopathic normal pressure hydrocephalus (iNPH) consenting patients (aged 67-88 years, median 74) were immuno-stained for Beta-amyloid (AMYB), Amyloid Precursor Protein (APP), total Tau, phosphorylated tau (AT8), Alpha Synuclein (AS), TDP- 43, P62 & GFAP. 5/11 patients had AMYB deposits, 2 diffuse plaques only, 3 diffuse and cored plaques; 1 also with amyloid angiopathy (CAA). Plaque neurites were labeled for APP and AT8 in all 3 patients with cored plaques; in one were these and neurofibrillary tangles labeled for total tau. The surface area covered by AMYB ranged from 12.8% to 0.08%. The presence of AMYB correlated with age (t, p=.02). Neither AS nor TDP-43 pathologies were identified. The density of cortical GFAP+ astrocytes showed a trend towards inverse correlation with age (r=-0.58, p=.06) but not with AMYB or AT8 pathologies. There were no significant correlations between pre-shunt Evans Ratio and MoCA scores and presence or amount of pathology. Improvement in ventriculomegaly (5/11) did not differ between patients with and without AMYB pathologies. Improvements in MoCA (6/8) were more common in patients without AMYB deposits (X2,p=.028; t, p=.04), but also in younger patients (t, p=.019). The patient with CAA improved, but the one with total tau pathology did not improve cognitively, although her gait did. In this preliminary study only AD-related pathology was found in iNPH. Cognitive improvement was associated with younger age and absence of amyloid deposits; however, a larger number of patients will be required to dissect these variables.

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Bruno, Francesco, Antonio Malvaso, Sonia Canterini, and Amalia Cecilia Bruni. "Antimicrobial Peptides (AMPs) in the Pathogenesis of Alzheimer’s Disease: Implications for Diagnosis and Treatment." Antibiotics 11, no. 6 (May 28, 2022): 726. http://dx.doi.org/10.3390/antibiotics11060726.

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Alzheimer’s disease (AD) represents the most frequent type of dementia in elderly people. There are two major forms of the disease: sporadic (SAD)—whose causes are not completely understood—and familial (FAD)—with clear autosomal dominant inheritance. The two main hallmarks of AD are extracellular deposits of amyloid-beta (Aβ) peptide and intracellular deposits of the hyperphosphorylated form of the tau protein (P-tau). An ever-growing body of research supports the infectious hypothesis of sporadic forms of AD. Indeed, it has been documented that some pathogens, such as herpesviruses and certain bacterial species, are commonly present in AD patients, prompting recent clinical research to focus on the characterization of antimicrobial peptides (AMPs) in this pathology. The literature also demonstrates that Aβ can be considered itself as an AMP; thus, representing a type of innate immune defense peptide that protects the host against a variety of pathogens. Beyond Aβ, other proteins with antimicrobial activity, such as lactoferrin, defensins, cystatins, thymosin β4, LL37, histatin 1, and statherin have been shown to be involved in AD. Here, we summarized and discussed these findings and explored the diagnostic and therapeutic potential of AMPs in AD.

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Moreira, Cristóvão, Torres, Carapeto, Rodrigues, Landrieu, Cordeiro, and Gomes. "Zinc Binding to Tau Influences Aggregation Kinetics and Oligomer Distribution." International Journal of Molecular Sciences 20, no. 23 (November 27, 2019): 5979. http://dx.doi.org/10.3390/ijms20235979.

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Metal ions are well known modulators of protein aggregation and are key players in Alzheimer’s Disease, being found to be associated to pathologic protein deposits in diseased brains. Therefore, understanding how metals influence amyloid aggregation is critical in establishing molecular mechanisms that underlie disease onset and progression. Here, we report data on the interaction of full-length human Tau protein with calcium and zinc ions, evidencing that Tau self-assembly is differently regulated, depending on the type of bound metal ion. We established that Tau binds 4 Zn2+ and 1 Ca2+ per monomer while using native mass spectrometry analysis, without inducing order or substantial conformational changes in the intrinsically disordered Tau, as determined by structural analysis using circular dichroism and Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopies. However, Tau aggregation is found to proceed differently in the calcium- and -zinc bound forms. While the rate of aggregation, as determined from thioflavin-T (ThT) fluorescence kinetics, is highly increased in both cases, the reaction proceeds via different mechanisms, as evidenced by the absence of the lag phase in the reaction of zinc-bound Tau. Monitoring Tau aggregation using native mass spectrometry indeed evidenced a distinct distribution of Tau conformers along the reaction, as confirmed by dynamic light scattering analysis. We propose that such differences arise from zinc binding at distinct locations within the Tau sequence that prompt both the rapid formation of seeding oligomers through interactions at high affinity sites within the repeat domains, as well as amorphous aggregation, through low affinity interactions with residues elsewhere in the sequence, including at the fuzzy coat domain.

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Bello-Medina, Paola C., Karina Corona-Cervantes, Norma Gabriela Zavala Torres, Antonio González, Marcel Pérez-Morales, Diego A. González-Franco, Astrid Gómez, Jaime García-Mena, Sofía Díaz-Cintra, and Gustavo Pacheco-López. "Chronic-Antibiotics Induced Gut Microbiota Dysbiosis Rescues Memory Impairment and Reduces β-Amyloid Aggregation in a Preclinical Alzheimer’s Disease Model." International Journal of Molecular Sciences 23, no. 15 (July 26, 2022): 8209. http://dx.doi.org/10.3390/ijms23158209.

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Alzheimer’s disease (AD) is a multifactorial pathology characterized by β-amyloid (Aβ) deposits, Tau hyperphosphorylation, neuroinflammatory response, and cognitive deficit. Changes in the bacterial gut microbiota (BGM) have been reported as a possible etiological factor of AD. We assessed in offspring (F1) 3xTg, the effect of BGM dysbiosisdysbiosis in mothers (F0) at gestation and F1 from lactation up to the age of 5 months on Aβ and Tau levels in the hippocampus, as well as on spatial memory at the early symptomatic stage of AD. We found that BGM dysbiosisdysbiosis with antibiotics (Abx) treatment in F0 was vertically transferred to their F1 3xTg mice, as observed on postnatal day (PD) 30 and 150. On PD150, we observed a delay in spatial memory impairment and Aβ deposits, but not in Tau and pTau protein in the hippocampus at the early symptomatic stage of AD. These effects are correlated with relative abundance of bacteria and alpha diversity, and are specific to bacterial consortia. Our results suggest that this specific BGM could reduce neuroinflammatory responses related to cerebral amyloidosis and cognitive deficit and activate metabolic pathways associated with the biosynthesis of triggering or protective molecules for AD.

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Zgórzyńska, Emilia, Klaudia Krawczyk, Patrycja Bełdzińska, and Anna Walczewska. "Molecular basis of proteinopathies: Etiopathology of dementia and motor disorders." Postępy Higieny i Medycyny Doświadczalnej 75 (June 18, 2021): 456–73. http://dx.doi.org/10.5604/01.3001.0014.9513.

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Neurodegenerative diseases are one of the most important medical and social problems affecting elderly people, the percentage of which is significantly increasing in the total world population. The cause of these diseases is the destruction of neurons by protein aggregates that form pathological deposits in neurons, glial cells and in the intercellular space. Proteins whose molecules are easily destabilized by point mutations or endogenous processes are alpha-synuclein (ASN), tau and TDP-43. Pathological forms of these proteins form characteristic aggregates, which accumulate in the neurons and are the cause of various forms of dementia and motor disorders. The most common causes of dementia are tauopathies. In primary tauopathies, which include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), and frontotemporal dementia (FTD), modified tau molecules disrupt axonal transport and protein distribution in neurons. Ultimately, the helical filaments and neurofibrillary tangles of tau lead to neuron death in various structures of the brain. In Alzheimer’s disease hyperphosphorylated tau tangles along with β amyloid plaques are responsible for the degeneration of the hippocampus, entorhinal cortex and amygdala. The most prevalent synucleinopathies are Parkinson’s disease, multiple system atrophy (MSA) and dementia with Lewy bodies, where there is a degeneration of neurons in the extrapyramidal tracts or, as in MSA, autonomic nerves. TDP-43 inclusions in the cytoplasm cause the degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) and in one of the frontotemporal dementia variant (FTLD-TDP). In this work ASN, tau and TDP-43 structures are described, as well as the genetic and sporadic factors that lead to the destabilization of molecules, their aggregation and incorrect distribution in neurons, which are the causes of neurodegenerative diseases.

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Hall, G. F., B. Chu, G. Lee, and J. Yao. "Human tau filaments induce microtubule and synapse loss in an in vivo model of neurofibrillary degenerative disease." Journal of Cell Science 113, no. 8 (April 15, 2000): 1373–87. http://dx.doi.org/10.1242/jcs.113.8.1373.

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The intracellular accumulation of tau protein and its aggregation into filamentous deposits is the intracellular hallmark of neurofibrillary degenerative diseases such as Alzheimer's Disease and familial tauopathies in which tau is now thought to play a critical pathogenic role. Until very recently, the lack of a cellular model in which human tau filaments can be experimentally generated has prevented direct investigation of the causes and consequences of tau filament formation in vivo. In this study, we show that human tau filaments formed in lamprey central neurons (ABCs) that chronically overexpress human tau resemble the ‘straight filaments’ seen in Alzheimer's Disease and other neurofibrillary conditions, and are distinguishable from neurofilaments by their ultrastructure, distribution and intracellular behavior. We also show that tau filament formation in ABCs is associated with a distinctive pattern of dendritic degeneration that closely resembles the cytopathology of human neurofibrillary degenerative disease. This pattern includes localized cytoskeletal disruption and aggregation of membranous organelles, distal dendritic beading, and the progressive loss of dendritic microtubules and synapses. These results suggest that tau filament formation may be responsible for many key cytopathological features of neurofibrillary degeneration, possibly via the loss of microtubule based intracellular transport.

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Muraoka, Satoshi, Mark P. Jedrychowski, Kiran Yanamandra, Seiko Ikezu, Steven P. Gygi, and Tsuneya Ikezu. "Proteomic Profiling of Extracellular Vesicles Derived from Cerebrospinal Fluid of Alzheimer’s Disease Patients: A Pilot Study." Cells 9, no. 9 (August 25, 2020): 1959. http://dx.doi.org/10.3390/cells9091959.

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Pathological hallmarks of Alzheimer’s disease (AD) are deposits of amyloid beta (Aβ) and hyper-phosphorylated tau aggregates in brain plaques. Recent studies have highlighted the importance of Aβ and tau-containing extracellular vesicles (EVs) in AD. We therefore examined EVs separated from cerebrospinal fluid (CSF) of AD, mild cognitive impairment (MCI), and control (CTRL) patient samples to profile the protein composition of CSF EV. EV fractions were separated from AD (n = 13), MCI (n = 10), and CTRL (n = 10) CSF samples using MagCapture Exosome Isolation kit. The CSF-derived EV proteins were identified and quantified by label-free and tandem mass tag (TMT)-labeled mass spectrometry. Label-free proteomics analysis identified 2546 proteins that were significantly enriched for extracellular exosome ontology by Gene Ontology analysis. Canonical Pathway Analysis revealed glia-related signaling. Quantitative proteomics analysis, moreover, showed that EVs expressed 1284 unique proteins in AD, MCI and CTRL groups. Statistical analysis identified three proteins—HSPA1A, NPEPPS, and PTGFRN—involved in AD progression. In addition, the PTGFRN showed a moderate correlation with amyloid plaque (rho = 0.404, p = 0.027) and tangle scores (rho = 0.500, p = 0.005) in AD, MCI and CTRL. Based on the CSF EV proteomics, these data indicate that three proteins, HSPA1A, NPEPPS and PTGFRN, may be used to monitor the progression of MCI to AD.

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Bruno, Rosalia, Laura Pirisinu, Geraldina Riccardi, Claudia D’Agostino, Elena De Cecco, Giuseppe Legname, Franco Cardone, et al. "Gerstmann–Sträussler–Scheinker Disease with F198S Mutation Induces Independent Tau and Prion Protein Pathologies in Bank Voles." Biomolecules 12, no. 10 (October 21, 2022): 1537. http://dx.doi.org/10.3390/biom12101537.

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Gerstmann–Sträussler–Scheinker disease (GSS) is a rare genetic prion disease. A large GSS kindred linked to the serine-for-phenylalanine substitution at codon 198 of the prion protein gene (GSS-F198S) is characterized by conspicuous accumulation of prion protein (PrP)-amyloid deposits and neurofibrillary tangles. Recently, we demonstrated the transmissibility of GSS-F198S prions to bank vole carrying isoleucine at 109 PrP codon (BvI). Here we investigated: (i) the transmissibility of GSS-F198S prions to voles carrying methionine at codon 109 (BvM); (ii) the induction of hyperphosphorylated Tau (pTau) in two vole lines, and (iii) compared the phenotype of GSS-F198S-induced pTau with pTau induced in BvM following intracerebral inoculation of a familial Alzheimer’s disease case carrying Presenilin 1 mutation (fAD-PS1). We did not detect prion transmission to BvM, despite the high susceptibility of BvI previously observed. Immunohistochemistry established the presence of induced pTau depositions in vole brains that were not affected by prions. Furthermore, the phenotype of pTau deposits in vole brains was similar in GSS-F198S and fAD-PS1. Overall, results suggest that, regardless of the cause of pTau deposition and its relationship with PrPSc in GSS-F198S human-affected brains, the two components possess their own seeding properties, and that pTau deposition is similarly induced by GSS-F198S and fAD-PS1.

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Mroczko, Groblewska, and Litman-Zawadzka. "The Role of Protein Misfolding and Tau Oligomers (TauOs) in Alzheimer′s Disease (AD)." International Journal of Molecular Sciences 20, no. 19 (September 20, 2019): 4661. http://dx.doi.org/10.3390/ijms20194661.

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Although the causative role of the accumulation of amyloid β 1–42 (Aβ42) deposits in the pathogenesis of Alzheimer′s disease (AD) has been under debate for many years, it is supposed that the toxicity soluble oligomers of Tau protein (TauOs) might be also the pathogenic factor acting on the initial stages of this disease. Therefore, we performed a thorough search for literature pertaining to our investigation via the MEDLINE/PubMed database. It was shown that soluble TauOs, especially granular forms, may be the most toxic form of this protein. Hyperphosphorylated TauOs can reduce the number of synapses by missorting into axonal compartments of neurons other than axon. Furthermore, soluble TauOs may be also responsible for seeding Tau pathology within AD brains, with probable link to AβOs toxicity. Additionally, the concentrations of TauOs in the cerebrospinal fluid (CSF) and plasma of AD patients were higher than in non-demented controls, and revealed a negative correlation with mini-mental state examination (MMSE) scores. It was postulated that adding the measurements of TauOs to the panel of CSF biomarkers could improve the diagnosis of AD.

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Streit, Wolfgang J., Jonas Rotter, Karsten Winter, Wolf Müller, Habibeh Khoshbouei, and Ingo Bechmann. "Droplet Degeneration of Hippocampal and Cortical Neurons Signifies the Beginning of Neuritic Plaque Formation." Journal of Alzheimer's Disease 85, no. 4 (February 15, 2022): 1701–20. http://dx.doi.org/10.3233/jad-215334.

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Background: Neuritic plaques contain neural and microglial elements, and amyloid-β protein (Aβ), but their pathogenesis remains unknown. Objective: Elucidate neuritic plaque pathogenesis. Methods: Histochemical visualization of hyperphosphorylated-tau positive (p-tau+) structures, microglia, Aβ, and iron. Results: Disintegration of large projection neurons in human hippocampus and neocortex presents as droplet degeneration: pretangle neurons break up into spheres of numerous p-tau+ droplets of various sizes, which marks the beginning of neuritic plaques. These droplet spheres develop in the absence of colocalized Aβ deposits but once formed become encased in diffuse Aβ with great specificity. In contrast, neurofibrillary tangles often do not colocalize with Aβ. Double-labelling for p-tau and microglia showed a lack of microglial activation or phagocytosis of p-tau+ degeneration droplets but revealed massive upregulation of ferritin in microglia suggesting presence of high levels of free iron. Perl’s Prussian blue produced positive staining of microglia, droplet spheres, and Aβ plaque cores supporting the suggestion that droplet degeneration of pretangle neurons in the hippocampus and cortex represents ferroptosis, which is accompanied by the release of neuronal iron extracellularly. Conclusion: Age-related iron accumulation and ferroptosis in the CNS likely trigger at least two endogenous mechanisms of neuroprotective iron sequestration and chelation, microglial ferritin expression and Aβ deposition, respectively, both contributing to the formation of neuritic plaques. Since neurofibrillary tangles and Aβ deposits colocalize infrequently, tangle formation likely does not involve release of neuronal iron extracellularly. In human brain, targeted deposition of Aβ occurs specifically in response to ongoing ferroptotic droplet degeneration thereby producing neuritic plaques.

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Fidziańska, Anna, and Zofia Glinka. "Rimmed vacuoles with beta-amyloid and tau protein deposits in the muscle of children with hereditary myopathy." Acta Neuropathologica 112, no. 2 (June 21, 2006): 185–93. http://dx.doi.org/10.1007/s00401-006-0079-3.

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Alvente, Sara, Gabriele Matteoli, Laura Molina-Porcel, Jon Landa, Mercedes Alba, Stefano Bastianini, Chiara Berteotti, et al. "Pilot Study of the Effects of Chronic Intracerebroventricular Infusion of Human Anti-IgLON5 Disease Antibodies in Mice." Cells 11, no. 6 (March 17, 2022): 1024. http://dx.doi.org/10.3390/cells11061024.

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Background: Anti-IgLON5 disease is a rare late-onset neurological disease associated with autoantibodies against IgLON5, neuronal accumulation of phosphorylated Tau protein (p-Tau), and sleep, respiratory, and motor alterations. Purpose: We performed a pilot study of whether the neuropathological and clinical features of anti-IgLON5 disease may be recapitulated in mice with chronic intracerebroventricular infusion of human anti-IgLON5 disease IgG (Pt-IgG). Methods: Humanized transgenic hTau mice expressing human Tau protein and wild-type (WT) control mice were infused intracerebroventricularly with Pt-IgG or with antibodies from a control subject for 14 days. The sleep, respiratory, and motor phenotype was evaluated at the end of the antibody infusion and at least 30 days thereafter, followed by immunohistochemical assessment of p-Tau deposition. Results: In female hTau and WT mice infused with Pt-IgG, we found reproducible trends of diffuse neuronal cytoplasmic p-Tau deposits in the brainstem and hippocampus, increased ventilatory period during sleep, and decreased inter-lick interval during wakefulness. These findings were not replicated on male hTau mice. Conclusion: The results of our pilot study suggest, but do not prove, that chronic ICV infusion of mice with Pt-IgG may elicit neuropathological, respiratory, and motor alterations. These results should be considered as preliminary until replicated in larger studies taking account of potential sex differences in mice.

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Ricci, Maria, Andrea Cimini, Riccardo Camedda, Agostino Chiaravalloti, and Orazio Schillaci. "Tau Biomarkers in Dementia: Positron Emission Tomography Radiopharmaceuticals in Tauopathy Assessment and Future Perspective." International Journal of Molecular Sciences 22, no. 23 (November 30, 2021): 13002. http://dx.doi.org/10.3390/ijms222313002.

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Abnormal accumulation of Tau protein is closely associated with neurodegeneration and cognitive impairment and it is a biomarker of neurodegeneration in the dementia field, especially in Alzheimer’s disease (AD); therefore, it is crucial to be able to assess the Tau deposits in vivo. Beyond the fluid biomarkers of tauopathy described in this review in relationship with the brain glucose metabolic patterns, this review aims to focus on tauopathy assessment by using Tau PET imaging. In recent years, several first-generation Tau PET tracers have been developed and applied in the dementia field. Common limitations of first-generation tracers include off-target binding and subcortical white-matter uptake; therefore, several institutions are working on developing second-generation Tau tracers. The increasing knowledge about the distribution of first- and second-generation Tau PET tracers in the brain may support physicians with Tau PET data interpretation, both in the research and in the clinical field, but an updated description of differences in distribution patterns among different Tau tracers, and in different clinical conditions, has not been reported yet. We provide an overview of first- and second-generation tracers used in ongoing clinical trials, also describing the differences and the properties of novel tracers, with a special focus on the distribution patterns of different Tau tracers. We also describe the distribution patterns of Tau tracers in AD, in atypical AD, and further neurodegenerative diseases in the dementia field.

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Villavicencio-Tejo, Francisca, Margrethe A. Olesen, Alejandra Aránguiz, and Rodrigo A. Quintanilla. "Activation of the Nrf2 Pathway Prevents Mitochondrial Dysfunction Induced by Caspase-3 Cleaved Tau: Implications for Alzheimer’s Disease." Antioxidants 11, no. 3 (March 8, 2022): 515. http://dx.doi.org/10.3390/antiox11030515.

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Alzheimer’s disease (AD) is characterized by memory and cognitive impairment, accompanied by the accumulation of extracellular deposits of amyloid β-peptide (Aβ) and the presence of neurofibrillary tangles (NFTs) composed of pathological forms of tau protein. Mitochondrial dysfunction and oxidative stress are also critical elements for AD development. We previously showed that the presence of caspase-3 cleaved tau, a relevant pathological form of tau in AD, induced mitochondrial dysfunction and oxidative damage in different neuronal models. Recent studies demonstrated that the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) plays a significant role in the antioxidant response promoting neuroprotection. Here, we studied the effects of Nrf2 activation using sulforaphane (SFN) against mitochondrial injury induced by caspase-3 cleaved tau. We used immortalized cortical neurons to evaluate mitochondrial bioenergetics and ROS levels in control and SFN-treated cells. Expression of caspase-3 cleaved tau induced mitochondrial fragmentation, depolarization, ATP loss, and increased ROS levels. Treatment with SFN for 24 h significantly prevented these mitochondrial abnormalities, and reduced ROS levels. Analysis of Western blots and rt-PCR studies showed that SFN treatment increased the expression of several Nrf2-related antioxidants genes in caspase-3 cleaved tau cells. These results indicate a potential role of the Nrf2 pathway in preventing mitochondrial dysfunction induced by pathological forms of tau in AD.

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Frost, Bess E., Wenyan Sun, Hanie Samimi, and Habil Zare. "JUMP AROUND, JUMP AROUND: TRANSPOSABLE ELEMENT ACTIVATION IN NEURODEGENERATIVE TAUOPATHY." Innovation in Aging 3, Supplement_1 (November 2019): S587. http://dx.doi.org/10.1093/geroni/igz038.2178.

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Abstract Transposable elements, or “jumping genes,” constitute ~45% of the human genome. We have identified transposable element activation as a key mediator of neurodegeneration in tauopathies, a group of disorders that are pathologically defined by deposits of tau protein in the brain. Cellular defenses that limit transposable element mobilization include 1) formation of silencing heterochromatin and 2) generation of piwi-interacting RNAs (piRNAs) that clear transposable element transcripts. Using genetic approaches in Drosophila models of tauopathy, we find evidence for a causal relationship between tau-induced heterochromatin decondensation and piRNA depletion, transposable element mobilization, and neurodegeneration. 3TC, an FDA-approved inhibitor of reverse transcriptase, suppresses transposable element mobilization and neuronal death in tau transgenic Drosophila. We detect a significant increase in transcripts of the human endogenous retrovirus class of transposable elements in postmortem human Alzheimer’s disease brains. Our data identify transposable element activation as a conserved, pharmacologically targetable driver of neurodegeneration in tauopathy.

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Giannakopoulos, P., S. Silhol, V. Jallageas, J. Mallet, N. Bons, C. Bouras, and P. Delaère. "Quantitative analysis of tau protein-immunoreactive accumulations and β amyloid protein deposits in the cerebral cortex of the mouse lemur, Microcebus murinus." Acta Neuropathologica 94, no. 2 (August 7, 1997): 131–39. http://dx.doi.org/10.1007/s004010050684.

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Okamura, Nobuyuki, Shozo Furumoto, Ryuichi Harada, Michelle Fodero-Tavoletti, Rachel S. Mulligan, Colin Masters, Kazuhiko Yanai, Yukitsuka Kudo, Christopher Rowe, and Victor Villemagne. "P1-307: In vivo detection of tau protein deposits in Alzheimer's disease using 18F-labeled 2-phenylquinoline derivatives." Alzheimer's & Dementia 9 (July 2013): P268. http://dx.doi.org/10.1016/j.jalz.2013.05.533.

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Cristóvão, Joana S., Renata Santos, and Cláudio M. Gomes. "Metals and Neuronal Metal Binding Proteins Implicated in Alzheimer’s Disease." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–13. http://dx.doi.org/10.1155/2016/9812178.

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Alzheimer’s disease (AD) is the most prevalent age-related dementia affecting millions of people worldwide. Its main pathological hallmark feature is the formation of insoluble protein deposits of amyloid-βand hyperphosphorylated tau protein into extracellular plaques and intracellular neurofibrillary tangles, respectively. Many of the mechanistic details of this process remain unknown, but a well-established consequence of protein aggregation is synapse dysfunction and neuronal loss in the AD brain. Different pathways including mitochondrial dysfunction, oxidative stress, inflammation, and metal metabolism have been suggested to be implicated in this process. In particular, a body of evidence suggests that neuronal metal ions such as copper, zinc, and iron play important roles in brain function in health and disease states and altered homeostasis and distribution as a common feature across different neurodegenerative diseases and aging. In this focused review, we overview neuronal proteins that are involved in AD and whose metal binding properties may underlie important biochemical and regulatory processes occurring in the brain during the AD pathophysiological process.

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Williams, Erik A., Declan McGuone, Matthew P. Frosch, Bradley T. Hyman, Nora Laver, and Anat Stemmer-Rachamimov. "Absence of Alzheimer Disease Neuropathologic Changes in Eyes of Subjects With Alzheimer Disease." Journal of Neuropathology & Experimental Neurology 76, no. 5 (March 30, 2017): 376–83. http://dx.doi.org/10.1093/jnen/nlx020.

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Alzheimer disease (AD) is the most common cause of dementia in the elderly, and is characterized by extracellular deposition of β-amyloid and intracellular accumulation of hyperphosphorylated tau protein in the brain. These pathologic findings are identified postmortem. Various visual deficits in AD have been reported and there have been conflicting reports, through imaging and pathology studies, regarding the presence of changes in the globe that mirror Alzheimer changes in the brain. Moreover, both macular degeneration and glaucoma have been variously characterized as having AD-related features. We examined one or both eyes from 19 autopsy cases, 17 of which had varying degrees of AD-related changes, and 2 of which were age-matched controls. Three cases had glaucoma and 4 had macular degeneration. Immunohistochemistry for tau, β-amyloid, TDP-43, ubiquitin, and α-synuclein showed no evidence of inclusions, deposits or other protein accumulation in any case, in any part of the globe. This finding suggests that regardless of the severity of changes seen in the brain in AD, there are no similar changes in the globe.

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Jaworski, Tomasz, Sebastian Kügler, and Fred Van Leuven. "Modeling of Tau-Mediated Synaptic and Neuronal Degeneration in Alzheimer's Disease." International Journal of Alzheimer's Disease 2010 (2010): 1–10. http://dx.doi.org/10.4061/2010/573138.

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Patients suffering from Alzheimer's disease (AD) are typified and diagnosed postmortem by the combined accumulations of extracellular amyloid plaques and of intracellular tauopathy, consisting of neuropil treads and neurofibrillary tangles in the somata. Both hallmarks are inseparable and remain diagnostic as described by Alois Alzheimer more than a century ago. Nevertheless, these pathological features are largely abandoned as being the actual pathogenic or neurotoxic factors. The previous, almost exclusive experimental attention on amyloid has shifted over the last 10 years in two directions. Firstly, from the “concrete” deposits of amyloid plaques to less well-defined soluble or pseudosoluble oligomers of the amyloid peptides, ranging from dimers to dodecamers and even larger aggregates. A second shift in research focus is from amyloid to tauopathy, and to their mutual relation. The role of Tau in the pathogenesis and disease progression is appreciated as leading to synaptic and neuronal loss, causing cognitive deficits and dementia. Both trends are incorporated in a modified amyloid cascade hypothesis, briefly discussed in this paper that is mainly concerned with the second aspect, that is, protein Tau and its associated fundamental questions.

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Uberti, Augusto F., Natalia Callai-Silva, Matheus V. C. Grahl, Angela R. Piovesan, Eduarda G. Nachtigall, Cristiane R. G. Furini, and Celia Regina Carlini. "Helicobacter pylori Urease: Potential Contributions to Alzheimer’s Disease." International Journal of Molecular Sciences 23, no. 6 (March 13, 2022): 3091. http://dx.doi.org/10.3390/ijms23063091.

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Alzheimer’s disease (AD) causes dementia and memory loss in the elderly. Deposits of beta-amyloid peptide and hyperphosphorylated tau protein are present in a brain with AD. A filtrate of Helicobacter pylori’s culture was previously found to induce hyperphosphorylation of tau in vivo, suggesting that bacterial exotoxins could permeate the blood–brain barrier and directly induce tau’s phosphorylation. H. pylori, which infects ~60% of the world population and causes gastritis and gastric cancer, produces a pro-inflammatory urease (HPU). Here, the neurotoxic potential of HPU was investigated in cultured cells and in rats. SH-SY5Y neuroblastoma cells exposed to HPU (50–300 nM) produced reactive oxygen species (ROS) and had an increased [Ca2+]i. HPU-treated BV-2 microglial cells produced ROS, cytokines IL-1β and TNF-α, and showed reduced viability. Rats received daily i.p., HPU (5 µg) for 7 days. Hyperphosphorylation of tau at Ser199, Thr205 and Ser396 sites, with no alterations in total tau or GSK-3β levels, and overexpression of Iba1, a marker of microglial activation, were seen in hippocampal homogenates. HPU was not detected in the brain homogenates. Behavioral tests were performed to assess cognitive impairments. Our findings support previous data suggesting an association between infection by H. pylori and tauopathies such as AD, possibly mediated by its urease.

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Trejo-Lopez, Jorge A., Zachary A. Sorrentino, Cara J. Riffe, Stefan Prokop, Dennis W. Dickson, Anthony T. Yachnis, and Benoit I. Giasson. "Generation and Characterization of Novel Monoclonal Antibodies Targeting p62/sequestosome-1 Across Human Neurodegenerative Diseases." Journal of Neuropathology & Experimental Neurology 79, no. 4 (February 3, 2020): 407–18. http://dx.doi.org/10.1093/jnen/nlaa007.

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Abstract Human neurodegenerative diseases can be characterized as disorders of protein aggregation. As a key player in cellular autophagy and the ubiquitin proteasome system, p62 may represent an effective immunohistochemical target, as well as mechanistic operator, across neurodegenerative proteinopathies. In this study, 2 novel mouse-derived monoclonal antibodies 5G3 and 2A5 raised against residues 360–380 of human p62/sequestosome-1 were characterized via immunohistochemical application upon human tissues derived from cases of C9orf72-expansion spectrum diseases, Alzheimer disease, progressive supranuclear palsy, Lewy body disease, and multiple system atrophy. 5G3 and 2A5 reliably highlighted neuronal dipeptide repeat, tau, and α-synuclein inclusions in a distribution similar to a polyclonal antibody to p62, phospho-tau antibodies 7F2 and AT8, and phospho-α-synuclein antibody 81A. However, antibodies 5G3 and 2A5 consistently stained less neuropil structures, such as tau neuropil threads and Lewy neurites, while 2A5 marked fewer glial inclusions in progressive supranuclear palsy. Both 5G3 and 2A5 revealed incidental astrocytic tau immunoreactivity in cases of Alzheimer disease and Lewy body disease with resolution superior to 7F2. Through their unique ability to highlight specific types of pathological deposits in neurodegenerative brain tissue, these novel monoclonal p62 antibodies may provide utility in both research and diagnostic efforts.

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Chiu, Ya-Jen, Te-Hsien Lin, Chiung-Mei Chen, Chih-Hsin Lin, Yu-Shan Teng, Chung-Yin Lin, Ying-Chieh Sun, et al. "Novel Synthetic Coumarin-Chalcone Derivative (E)-3-(3-(4-(Dimethylamino)Phenyl)Acryloyl)-4-Hydroxy-2H-Chromen-2-One Activates CREB-Mediated Neuroprotection in Aβ and Tau Cell Models of Alzheimer’s Disease." Oxidative Medicine and Cellular Longevity 2021 (November 13, 2021): 1–19. http://dx.doi.org/10.1155/2021/3058861.

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Abnormal accumulations of misfolded Aβ and tau proteins are major components of the hallmark plaques and neurofibrillary tangles in the brains of Alzheimer’s disease (AD) patients. These abnormal protein deposits cause neurodegeneration through a number of proposed mechanisms, including downregulation of the cAMP-response-element (CRE) binding protein 1 (CREB) signaling pathway. Using CRE-GFP reporter cells, we investigated the effects of three coumarin-chalcone derivatives synthesized in our lab on CREB-mediated gene expression. Aβ-GFP- and ΔK280 tauRD-DsRed-expressing SH-SY5Y cells were used to evaluate these agents for possible antiaggregative, antioxidative, and neuroprotective effects. Blood-brain barrier (BBB) penetration was assessed by pharmacokinetic studies in mice. Of the three tested compounds, (E)-3-(3-(4-(dimethylamino)phenyl)acryloyl)-4-hydroxy-2H-chromen-2-one (LM-021) was observed to increase CREB-mediated gene expression through protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and extracellular signal-regulated kinase (ERK) in CRE-GFP reporter cells. LM-021 exhibited antiaggregative, antioxidative, and neuroprotective effects mediated by the upregulation of CREB phosphorylation and its downstream brain-derived neurotrophic factor and BCL2 apoptosis regulator genes in Aβ-GFP- and ΔK280 tauRD-DsRed-expressing SH-SY5Y cells. Blockage of the PKA, CaMKII, or ERK pathway counteracted the beneficial effects of LM-021. LM-021 also exhibited good BBB penetration ability, with brain to plasma ratio of 5.3%, in in vivo pharmacokinetic assessment. Our results indicate that LM-021 works as a CREB enhancer to reduce Aβ and tau aggregation and provide neuroprotection. These findings suggest the therapeutic potential of LM-021 in treating AD.

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van de Nes, J. A. P., S. Konermann, R. Nafe, and D. F. Swaab. "β-Protein/A4 deposits are not associated with hyperphosphorylated tau in somatostatin neurons in the hypothalamus of Alzheimer’s disease patients." Acta Neuropathologica 111, no. 2 (February 2006): 126–38. http://dx.doi.org/10.1007/s00401-005-0018-8.

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Areza-Fegyveres, Renata, Sergio Rosemberg, Rosa Maria R. P. S. Castro, Claudia Sellitto Porto, Valéria Santoro Bahia, Paulo Caramelli, and Ricardo Nitrini. "Dementia Pugilistica with clinical features of Alzheimer's disease." Arquivos de Neuro-Psiquiatria 65, no. 3b (September 2007): 830–33. http://dx.doi.org/10.1590/s0004-282x2007000500019.

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A 61-year-old ex-boxer presented with a three-year history of progressive memory decline. During a seven-year follow-up period, there was a continuous cognitive decline, very similar to that usually observed in Alzheimer's disease. Parkinsonian, pyramidal or cerebellar signs were conspicuously absent. Neuropathological examination revealed the typical features of dementia pugilistica: cavum septi pellucidi with multiple fenestrations, numerous neurofibrillary tangles in the cerebral isocortex and hippocampus (and rare senile plaques). Immunohistochemistry disclosed a high number of tau protein deposits and scarce beta-amyloid staining. This case shows that dementia pugilistica may present with clinical features practically undistinguishable from Alzheimer's disease.

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Scialò, Carlo, Elena De Cecco, Paolo Manganotti, and Giuseppe Legname. "Prion and Prion-Like Protein Strains: Deciphering the Molecular Basis of Heterogeneity in Neurodegeneration." Viruses 11, no. 3 (March 14, 2019): 261. http://dx.doi.org/10.3390/v11030261.

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Increasing evidence suggests that neurodegenerative disorders share a common pathogenic feature: the presence of deposits of misfolded proteins with altered physicochemical properties in the Central Nervous System. Despite a lack of infectivity, experimental data show that the replication and propagation of neurodegenerative disease-related proteins including amyloid-β (Aβ), tau, α-synuclein and the transactive response DNA-binding protein of 43 kDa (TDP-43) share a similar pathological mechanism with prions. These observations have led to the terminology of “prion-like” to distinguish between conditions with noninfectious characteristics but similarities with the prion replication and propagation process. Prions are considered to adapt their conformation to changes in the context of the environment of replication. This process is known as either prion selection or adaptation, where a distinct conformer present in the initial prion population with higher propensity to propagate in the new environment is able to prevail over the others during the replication process. In the last years, many studies have shown that prion-like proteins share not only the prion replication paradigm but also the specific ability to aggregate in different conformations, i.e., strains, with relevant clinical, diagnostic and therapeutic implications. This review focuses on the molecular basis of the strain phenomenon in prion and prion-like proteins.

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Decourt, Boris, Debomoy K. Lahiri, and Marwan N. Sabbagh. "Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease." Current Alzheimer Research 14, no. 4 (February 16, 2017): 412–25. http://dx.doi.org/10.2174/1567205013666160930110551.

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Alzheimer’s disease (AD) affects an estimated 44 million individuals worldwide, yet no therapeutic intervention is available to stop the progression of the dementia. Neuropathological hallmarks of AD are extracellular deposits of amyloid beta (Aβ) peptides assembled in plaques, intraneuronal accumulation of hyperphosphorylated tau protein forming tangles, and chronic inflammation. A pivotal molecule in inflammation is the pro-inflammatory cytokine TNF-α. Several lines of evidence using genetic and pharmacological manipulations indicate that TNF-α signaling exacerbates both Aβ and tau pathologies in vivo. Interestingly, preventive and intervention anti-inflammatory strategies demonstrated a reduction in brain pathology and an amelioration of cognitive function in rodent models of AD. Phase I and IIa clinical trials suggest that TNF-α inhibitors might slow down cognitive decline and improve daily activities in AD patients. In the present review, we summarize the evidence pointing towards a beneficial role of anti-TNF-α therapies to prevent or slow the progression of AD. We also present possible physical and pharmacological interventions to modulate TNF-α signaling in AD subjects along with their limitations.

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Franco, Aitor, Lorea Velasco-Carneros, Naiara Alvarez, Natalia Orozco, Fernando Moro, Adelina Prado, and Arturo Muga. "Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase." Cells 10, no. 10 (October 14, 2021): 2745. http://dx.doi.org/10.3390/cells10102745.

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Neurodegenerative diseases (NDs) are increasingly positioned as leading causes of global deaths. The accelerated aging of the population and its strong relationship with neurodegeneration forecast these pathologies as a huge global health problem in the upcoming years. In this scenario, there is an urgent need for understanding the basic molecular mechanisms associated with such diseases. A major molecular hallmark of most NDs is the accumulation of insoluble and toxic protein aggregates, known as amyloids, in extracellular or intracellular deposits. Here, we review the current knowledge on how molecular chaperones, and more specifically a ternary protein complex referred to as the human disaggregase, deals with amyloids. This machinery, composed of the constitutive Hsp70 (Hsc70), the class B J-protein DnaJB1 and the nucleotide exchange factor Apg2 (Hsp110), disassembles amyloids of α-synuclein implicated in Parkinson’s disease as well as of other disease-associated proteins such as tau and huntingtin. We highlight recent studies that have led to the dissection of the mechanism used by this chaperone system to perform its disaggregase activity. We also discuss whether this chaperone-mediated disassembly mechanism could be used to solubilize other amyloidogenic substrates. Finally, we evaluate the implications of the chaperone system in amyloid clearance and associated toxicity, which could be critical for the development of new therapies.

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Franco, Aitor, Lorea Velasco-Carneros, Naiara Alvarez, Natalia Orozco, Fernando Moro, Adelina Prado, and Arturo Muga. "Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase." Cells 10, no. 10 (October 14, 2021): 2745. http://dx.doi.org/10.3390/cells10102745.

Full text

Abstract:

Neurodegenerative diseases (NDs) are increasingly positioned as leading causes of global deaths. The accelerated aging of the population and its strong relationship with neurodegeneration forecast these pathologies as a huge global health problem in the upcoming years. In this scenario, there is an urgent need for understanding the basic molecular mechanisms associated with such diseases. A major molecular hallmark of most NDs is the accumulation of insoluble and toxic protein aggregates, known as amyloids, in extracellular or intracellular deposits. Here, we review the current knowledge on how molecular chaperones, and more specifically a ternary protein complex referred to as the human disaggregase, deals with amyloids. This machinery, composed of the constitutive Hsp70 (Hsc70), the class B J-protein DnaJB1 and the nucleotide exchange factor Apg2 (Hsp110), disassembles amyloids of α-synuclein implicated in Parkinson’s disease as well as of other disease-associated proteins such as tau and huntingtin. We highlight recent studies that have led to the dissection of the mechanism used by this chaperone system to perform its disaggregase activity. We also discuss whether this chaperone-mediated disassembly mechanism could be used to solubilize other amyloidogenic substrates. Finally, we evaluate the implications of the chaperone system in amyloid clearance and associated toxicity, which could be critical for the development of new therapies.

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Journal articles on the topic 'Tau protein deposits'

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