The six brain‐specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(5), P. 3606 - 3628

Published: March 31, 2024

Alternative splicing of the human MAPT gene generates six brain-specific TAU isoforms. Imbalances in isoform ratio can lead to neurodegenerative diseases, underscoring need for precise control over balance. Tauopathies, characterized by intracellular aggregates hyperphosphorylated TAU, exhibit extensive neurodegeneration and be classified isoforms present pathological accumulations.

Language: Английский

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Disentangling tau: One protein, many therapeutic approaches

Neurotherapeutics, Journal Year: 2024, Volume and Issue: 21(2), P. e00321 - e00321

Published: Jan. 25, 2024

The tauopathies encompass over 20 adult neurodegenerative diseases and are characterized by the dysfunction accumulation of insoluble tau protein. Among them, Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy collectively impact millions patients their families worldwide. Despite years drug development using a variety mechanisms action, no therapeutic directed against has been approved for clinical use. This raises important questions about our current model pathology invites thoughtful consideration approach to nonclinical models trial design. In this article, we review what is known biology genetics tau, placing it in context failed trials. We highlight potential reasons lack success date offer suggestions new pathways development. Overall, viewpoint future optimistic group diseases.

Language: Английский

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Genetic forms of tauopathies: inherited causes and implications of Alzheimer’s disease-like TAU pathology in primary and secondary tauopathies

Journal of Neurology, Journal Year: 2024, Volume and Issue: 271(6), P. 2992 - 3018

Published: March 30, 2024

Abstract Tauopathies are a heterogeneous group of neurologic diseases characterized by pathological axodendritic distribution, ectopic expression, and/or phosphorylation and aggregation the microtubule-associated protein TAU, encoded gene MAPT . Neuronal dysfunction, dementia, neurodegeneration common features these often detrimental diseases. A neurodegenerative disease is considered primary tauopathy when mutations/haplotypes its cause TAU main feature. In case pathology observed but superimposed another hallmark, condition classified as secondary tauopathy. some tauopathies (e.g. -associated frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Alzheimer's (AD)) recognized significant pathogenic driver disease. many tauopathies, including Parkinson's (PD) Huntington's (HD), suggested to contribute development in others Niemann-Pick (NPC)) may only be bystander. The genetic mechanisms underlying not fully understood. this review, predispositions variants associated with both examined detail, assessing evidence for role conditions. We highlight less forms increase awareness disorders involvement their pathology. This approach contributes deeper understanding conditions also lay groundwork potential TAU-based therapeutic interventions various tauopathies.

Language: Английский

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The Enigma of Tau Protein Aggregation: Mechanistic Insights and Future Challenges

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4969 - 4969

Published: May 2, 2024

Tau protein misfolding and aggregation are pathological hallmarks of Alzheimer's disease over twenty neurodegenerative disorders. However, the molecular mechanisms tau in vivo remain incompletely understood. There two types aggregates brain: soluble (oligomers protofibrils) insoluble filaments (fibrils). Compared to filamentous aggregates, more toxic exhibit prion-like transmission, providing seeds for templated misfolding. Curiously, its native state, is a highly soluble, heat-stable that does not form fibrils by itself, even when hyperphosphorylated. In vitro studies have found negatively charged molecules such as heparin, RNA, or arachidonic acid generally required induce aggregation. Two recent breakthroughs provided new insights into mechanisms. First, an intrinsically disordered protein, undergo liquid-liquid phase separation (LLPS) both inside cells. Second, cryo-electron microscopy has revealed diverse fibrillar conformations associated with different Nonetheless, only core structurally resolved, remainder appears "fuzzy coat". From this review, it further (1) clarify role LLPS aggregation; (2) unveil structural features aggregates; (3) understand involvement fuzzy coat regions oligomer fibril formation.

Language: Английский

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Identification of high-performing antibodies for the reliable detection of Tau proteoforms by Western blotting and immunohistochemistry

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

Published: May 18, 2024

Antibodies are essential research tools whose performance directly impacts conclusions and reproducibility. Owing to its central role in Alzheimer's disease other dementias, hundreds of distinct antibody clones have been developed against the microtubule-associated protein Tau multiple proteoforms. Despite this breadth offer, limited understanding their poor selectivity hindered progress. Here, we validate a large panel antibodies by Western blot (79 reagents) immunohistochemistry (35 reagents). We address reagents' ability detect target proteoform, selectivity, impact phosphorylation on binding human brain samples. While most detected at high levels, many failed it lower, endogenous levels. By WB, non-selective proteins affected over half tested, with several cross-reacting related MAP2 protein, whereas "oligomeric Tau" T22 reacted monomeric thus calling into question specificity oligomers. presumption that "total" agnostic post-translational modifications, found partially inhibits for such antibodies, including popular Tau-5 clone. further combine high-sensitivity reagents, mass-spectrometry proteomics cDNA sequencing demonstrate presumptive "knockout" cells continue express residual arising through exon skipping, providing evidence previously unappreciated gene plasticity. Finally, probing samples revealed presence C-term-truncated versions all main isoforms both control tauopathy donors. Ultimately, identify validated can be employed blotting and/or reliably even low levels expression selectivity. This work represents an extensive resource will enable re-interpretation published data, improve reproducibility research, overall accelerate scientific

Language: Английский

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Cellular and molecular mechanisms of pathological tau phosphorylation in traumatic brain injury: implications for chronic traumatic encephalopathy

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

Published: May 10, 2025

Abstract Tau protein plays a critical role in the physiological functioning of central nervous system by providing structural integrity to cytoskeletal architecture neurons and glia through microtubule assembly stabilization. Under certain pathological conditions, tau is aberrantly phosphorylated aggregates into neurotoxic fibrillary tangles. The aggregation cell-to-cell propagation leads progressive deterioration system. clinical entity traumatic brain injury (TBI) ranges from mild severe can promote inducing cellular mechanisms signalling pathways that increase phosphorylation aggregation. Chronic encephalopathy (CTE), which consequence repetitive TBI, unique tauopathy characterized located at depths sulci surrounding blood vessels. leading increased CTE remain be fully defined but are likely result primary secondary sequelae associated with TBI. includes physical mechanical damage resulting head impact accompanying forces cause blood–brain barrier disruption axonal shearing, primes more vulnerable subsequent mechanisms. A complex interplay neuroinflammation, oxidative stress, excitotoxicity, mitochondrial dysfunction activate kinase cell death pathways, increasing phosphorylation, neurodegeneration. In this review, we explore most recent insights TBI propose how multiple converge on may contribute progression. Graphical

Language: Английский

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The Role of Tau in Neuronal Function and Neurodegeneration

Neurology International, Journal Year: 2025, Volume and Issue: 17(5), P. 75 - 75

Published: May 13, 2025

Tau protein plays a pivotal role in maintaining neuronal structure and function through its regulation of microtubule stability polarity. Encoded by the MAPT gene, exists multiple isoforms due to alternative mRNA splicing, with differential expression central peripheral nervous systems. In healthy neurons, tau is selectively localized translated axons, process tightly regulated untranslated regions (UTRs) RNA-binding proteins such as HuD FMRP. Pathologically, undergoes hyperphosphorylation, misfolding, aggregation, which contribute neurodegeneration range disorders collectively known tauopathies. Alzheimer’s disease (AD) most prevalent tauopathy, where abnormal accumulation temporal frontal lobes correlates cognitive decline behavioral symptoms. Other tauopathies, including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Frontotemporal Dementia Parkinsonism (FTDP-17), Pick’s disease, are distinguished predominance specific (3R or 4R), cellular distribution, affected brain regions. Notably, astroglial tauopathies highlight pathological glial cells, expanding understanding beyond neurons. Despite advances imaging biomarkers (e.g., Tau-PET) molecular diagnostics, effective disease-modifying therapies for remain elusive. Ongoing research targets immunotherapies, splicing modulators, kinase inhibitors, antisense oligonucleotides, aiming mitigate pathology deleterious effects. Understanding multifaceted roles contexts critical developing future therapeutic strategies against

Language: Английский

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Metal Toxicity and Dementia Including Frontotemporal Dementia: Current State of Knowledge

Antioxidants, Journal Year: 2024, Volume and Issue: 13(8), P. 938 - 938

Published: Aug. 1, 2024

Frontotemporal dementia (FTD) includes a number of neurodegenerative diseases, often with early onset (before 65 years old), characterized by progressive, irreversible deficits in behavioral, linguistic, and executive functions, which are difficult to diagnose due their similar phenotypic characteristics other dementias psychiatric disorders. The genetic contribution is utmost importance, although environmental risk factors also play role its pathophysiology. In fact, some metals known produce free radicals, which, accumulating the brain over time, can induce oxidative stress, inflammation, protein misfolding, all these being key features FTD conditions. Therefore, present review aims summarize current evidence about FTD-mainly dealing toxic metal exposure-since identification such potential lead diagnosis promotion policies interventions. This would allow us, reducing exposure pollutants, potentially affect society at large positive manner, decreasing burden conditions on affected individuals overall. Future perspectives, including application Artificial Intelligence principles field, related found so far, introduced.

Language: Английский

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Distinct involvement of the cranial and spinal nerves in progressive supranuclear palsy

Brain, Journal Year: 2023, Volume and Issue: 147(4), P. 1399 - 1411

Published: Nov. 16, 2023

Abstract The most frequent neurodegenerative proteinopathies include diseases with deposition of misfolded tau or α-synuclein in the brain. Pathological protein aggregates PNS are well-recognized α-synucleinopathies and have recently attracted attention as a diagnostic biomarker. However, there is paucity observations tauopathies. To characterize involvement tauopathies, we investigated pathology cranial spinal nerves (PNS-tau) 54 tauopathy cases [progressive supranuclear palsy (PSP), n = 15; Alzheimer’s disease (AD), 18; chronic traumatic encephalopathy (CTE), 5; corticobasal degeneration (CBD), 6; Pick’s disease, 9; limbic-predominant neuronal inclusion body 4-repeat (LNT), 1] using immunohistochemistry, Gallyas silver staining, biochemistry, seeding assays. Most PSP revealed phosphorylated immunoreactive deposits follows: (number tau-positive cases/available cases) III: 7/8 (88%); IX/X: 10/11 (91%); XII: 6/6 (100%); anterior roots: 10/10 (100%). inclusions often showed structures fibrillary (neurofibrillary tangle-like) morphology axon that were also recognized staining. CBD rarely fine granular non-argyrophilic deposits. In contrast, was not evident AD, CTE cases. single LNT case PNS. PSP, severity PNS-tau correlated corresponding nuclei, although, occasionally, p-tau present but related brainstem nuclei. Not surprisingly, presented eye movement disorder bulbar symptoms, some lower-motor neuron signs. Using biosensor cells, for first time demonstrated capacity conclusion, prominent distinguishes from other morphological differences between suggest could reflect central nervous system. high frequency early presence lesions may clinical biomarker relevance.

Language: Английский

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The unique properties of Big tau in the visual system

Cytoskeleton, Journal Year: 2024, Volume and Issue: 81(9-10), P. 488 - 499

Published: May 18, 2024

Tau is a microtubule associated protein that plays important roles in regulating the properties of microtubules and axonal transport, as well tauopathies with toxic aggregates leading to neurodegenerative diseases. It encoded by MAPT gene forming multiple isoforms (45-60 kDa) alternative splicing which are developmentally regulated. The high molecular weight (MW) tau isoform 105 kDa, termed Big tau, was originally discovered peripheral nervous system (PNS) but later found selective CNS areas. contains an additional large exon 4a generating long projecting domain about 250 amino acids. Here we investigated visual rats, its distribution retinal ganglion cells optic nerve developmental regulation using biochemical, histological analyses. We expresses 95 kDa (termed middle MW) containing exons 4a, 6 10 defines 4 microtubule-binding repeats (4R). lacks 2/3 shares extensive phosphorylation characteristic other isoforms. Importantly, early development only low MW (3R) switching both (4R) adult neurons their corresponding axons. This unique structure expression pattern hypothesize specific different from what has been previously described PNS areas system.

Language: Английский

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