Cellular and pathological functions of tau

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(11), P. 845 - 864

Published: July 16, 2024

Language: Английский

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Tau fibrils induce nanoscale membrane damage and nucleate cytosolic tau at lysosomes

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(22)

Published: May 23, 2024

The prion-like spread of protein aggregates is a leading hypothesis for the propagation neurofibrillary lesions in brain, including tau inclusions associated with Alzheimer’s disease. mechanisms cellular uptake seeds and subsequent nucleated polymerization cytosolic are major questions field, potential coupling between entry nucleation has been little explored. We found that primary astrocytes neurons, endocytosis leads to their accumulation lysosomes. This turn lysosomal swelling, deacidification, recruitment ESCRT proteins, but not Galectin-3, membrane. These observations consistent nanoscale damage Live cell imaging STORM superresolution microscopy further show occurs primarily at lysosome membrane under these conditions. data suggest escape from lysosomes via rather than wholesale rupture commences as soon fibril ends emerge

Language: Английский

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Alzheimer’s disease and its treatment–yesterday, today, and tomorrow

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: May 24, 2024

Alois Alzheimer described the first patient with Alzheimer’s disease (AD) in 1907 and today AD is most frequently diagnosed of dementias. a multi-factorial neurodegenerative disorder familial, life style comorbidity influences impacting global population more than 47 million projected escalation by 2050 to exceed 130 million. In USA demographic encompasses approximately six individuals, expected increase surpass 13 2050, antecedent phase AD, recognized as mild cognitive impairment (MCI), involves nearly 12 individuals. The economic outlay for management AD-related decline estimated at 355 billion USD. addition, intensifying prevalence cases countries modest intermediate income further enhances urgency therapeutically cost-effective treatments improving quality patients their families. This narrative review evaluates pathophysiological basis an initial focus on therapeutic efficacy limitations existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, N-methyl-D-aspartate receptor (NMDA) allosteric modulator, memantine. hypothesis amyloid-β (Aβ) tau are appropriate targets have potential halt progress critically analyzed particular clinical trial data anti-Aβ monoclonal antibodies (MABs), namely, aducanumab, lecanemab donanemab. challenges dogma targeting Aβ will benefit majority subjects MABs unlikely be “magic bullet”. A comparison benefits disadvantages different classes forms determining new directions research alternative drug undergoing pre-clinical assessments. we discuss stress importance treatment co-morbidities, including hypertension, diabetes, obesity depression known risk developing AD.

Language: Английский

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Similar brain proteomic signatures in Alzheimer’s disease and epilepsy

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 147(1)

Published: Jan. 30, 2024

Abstract The prevalence of epilepsy is increased among Alzheimer’s Disease (AD) patients and cognitive impairment common people with epilepsy. Epilepsy AD are linked but the shared pathophysiological changes remain poorly defined. We aim to identify protein differences associated using published proteomics datasets. observed a highly significant overlap in AD: 89% (689/777) proteins altered hippocampus were significantly advanced AD. Of both AD, 340 same direction, while 216 opposite direction. Synapse mitochondrial markedly decreased suggesting disease mechanisms. In contrast, ribosome Notably, many interact tau or regulated by expression. This suggests that likely mediates Immunohistochemistry for Aβ multiple phosphorylated species (pTau396/404, pTau217, pTau231) showed trend intraneuronal pTau217 pTau231 no aggregates amyloid plaques hippocampal sections. Our results provide insights into mechanisms highlights potential role mediating pathological

Language: Английский

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Cryo-EM structures of amyloid-β and tau filaments in Down syndrome

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: 31(6), P. 903 - 909

Published: March 29, 2024

Abstract Adult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and regarding the structure of amyloid-β (Aβ) tau filaments unknown. Here we report Aβ from two brains. We found 40 (types IIIa IIIb) that differ those previously reported sporadic types 42 (I II) identical to familial AD. Tau (paired helical straight filaments) were AD, supporting notion common mechanism through which amyloids trigger aggregation tau. This knowledge important for understanding assessing whether adults could be included clinical trials.

Language: Английский

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VCP regulates early tau seed amplification via specific cofactors

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 7, 2025

Abstract Background Neurodegenerative tauopathies may progress based on seeding by pathological tau assemblies, whereby an aggregate is released from one cell, gains entry to adjacent or connected and serves as a specific template for its own replication in the cytoplasm. Seeding into complex cytoplasmic milieu happens within hours, implying existence of unknown factors that regulate this process. Methods We used proximity labeling identify proteins control seed amplification 5 h exposure. fused split-APEX2 C-terminus repeat domain (RD) reconstitute peroxidase activity after seeded intracellular aggregation. Valosin containing protein (VCP/p97) was top hit. VCP harbors dominant mutations underlie two neurodegenerative diseases, multisystem proteinopathy vacuolar tauopathy, but mechanistic role unclear. immortalized cells human neurons study effects seeding. exposed fibrils brain homogenates cell culture media measured uptake induction aggregation following various genetic pharmacological manipulations VCP. Results knockdown reduced Chemical inhibitors had opposing HEK293T biosensor neurons: ML-240 increased efficiency, whereas NMS-873 decreased it. The only functioned when administered 8 exposure, indicating early processing. screened 30 co-factors knockout knockdown. Reduction ATXN3, NSFL1C, UBE4B, NGLY1, OTUB1 seeding, did NPLOC4, which also uniquely soluble levels. By contrast, reduction FAF2 Conclusions Divergent chemical cofactor indicate regulates This consistent with processing centered directs seeds acutely towards degradation vs. amplification.

Language: Английский

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Guidelines for bioinformatics of single-cell sequencing data analysis in Alzheimer’s disease: review, recommendation, implementation and application

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: March 2, 2022

Abstract Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive cognitive impairment and neurodegeneration. Extensive clinical genomic studies have revealed biomarkers, risk factors, pathways, targets AD in past decade. However, exact molecular basis development progression remains elusive. The emerging single-cell sequencing technology can potentially provide cell-level insights into disease. Here we systematically review state-of-the-art bioinformatics approaches to analyze data their applications 14 major directions, including 1) quality control normalization, 2) dimension reduction feature extraction, 3) cell clustering analysis, 4) type inference annotation, 5) differential expression, 6) trajectory inference, 7) copy number variation 8) integration multi-omics, 9) epigenomic 10) gene network 11) prioritization subpopulations, 12) integrative analysis human mouse sc-RNA-seq data, 13) spatial transcriptomics, 14) comparison single model studies. We also address challenges using postmortem tissues outline future developments analysis. Importantly, implemented our recommended workflow for each analytic direction applied them a large nucleus RNA-sequencing (snRNA-seq) dataset AD. Key results are reported while scripts shared with research community through GitHub. In summary, this comprehensive provides various offers specific guidelines study design variety directions. accompanied software tools will serve as valuable resource studying cellular mechanisms AD, other diseases, or biological systems at level.

Language: Английский

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Tau interactome and RNA binding proteins in neurodegenerative diseases

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Oct. 17, 2022

Pathological tau aggregation is a primary neuropathological feature of many neurodegenerative diseases. Intriguingly, despite the common presence aggregates in these diseases affected brain regions, clinical symptoms, and morphology, conformation, isoform ratio present varies widely. The tau-mediated disease mechanisms that drive are still unknown. Tau interactome studies critically important for understanding tauopathy. They reveal interacting partners define pathways, interactions provide potential insight into cellular environment protein during pathological aggregation. Here we combined analysis 12 human tissue, cell culture models rodent disease. Together, identified 2084 proteins interact with tissue 1152 Our revealed consistent enrichment between involved RNA binding, ribosome, proteasome function. Comparison substantial differences two species. We also performed second to identify enriched neurons containing granulovacuolar degeneration or neurofibrillary tangle pathology. These results timed dysregulation as pathology develops. binding proteins, particularly HNRNPs, emerged early disease-associated interactors therefore may have an role driving

Language: Английский

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Cerebrospinal fluid biomarker panel of synaptic dysfunction in Alzheimer's disease and other neurodegenerative disorders

Alzheimer s & Dementia, Journal Year: 2022, Volume and Issue: 19(5), P. 1775 - 1784

Published: Oct. 14, 2022

Abstract Introduction Synaptic degeneration is a key part of the pathophysiology neurodegenerative diseases, and biomarkers reflecting pathological alterations are greatly needed. Method Seventeen synaptic proteins were quantified in pathology‐confirmed cerebrospinal fluid cohort patients with Alzheimer's disease (AD; n = 63), frontotemporal lobar (FTLD; 53), Lewy body spectrum disorders (LBD; 21), as well healthy controls (HC; 48). Results Comparisons revealed four distinct patterns: markers decreased across all conditions compared to HC (the neuronal pentraxins), increased (14‐3‐3 zeta/delta), selectively AD other (neurogranin beta‐synuclein), LBD FTLD (AP2B1 syntaxin‐1B). Discussion Several may serve for dysfunction AD, LBD, FTLD. Additionally, differential patterns protein seem be present diseases. Highlights A panel using mass spectrometry. We disease, degeneration, disorders. Pathology was confirmed by autopsy or familial mutations. discovered cognitive decline. found

Language: Английский

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Redox signaling and metabolism in Alzheimer's disease

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: Nov. 3, 2022

Reduction and oxidation reactions are essential for biochemical processes. They part of metabolic pathways signal transduction. Reactive oxygen species (ROS) as second messengers oxidative modifications cysteinyl (Cys) residues key to transduce translate intracellular intercellular signals. Dysregulation cellular redox signaling is known distress, which has been linked various pathologies, including neurodegeneration. Alzheimer's disease (AD) a neurodegenerative pathology both, abnormal amyloid precursor protein (APP) processing, generating Aβ peptide, Tau hyperphosphorylation aggregation. Signs distress in AD include: increase ROS (H 2 O , •− ), decrease the levels or activities antioxidant enzymes, macromolecules related elevated production, changes mitochondrial homeostasis phosphorylation. Interestingly, Cys present APP form disulfide bonds that important intermolecular interactions might be involved aggregation Aβ. Moreover, two some isoforms have shown stabilization its interaction with microtubules. Future research will show complexities Tau, interactome, role play progression AD. The specific modification also tightly connected regulation pathways. Many these found altered AD, even at very early stages. In order analyze complex underlying mechanisms, several models developed, animal models, 2D 3D cell culture, ex-vivo studies patient samples. use along innovative, new analysis techniques further understand importance component identification therapeutic targets future.

Language: Английский

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