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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Alzheimer’s Disease as Type 3 Diabetes: Understanding the Link and Implications

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(22), P. 11955 - 11955

Published: Nov. 7, 2024

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two prevalent conditions that present considerable public health issue in aging populations worldwide. Recent research has proposed a novel conceptualization of AD as "type 3 diabetes", highlighting the critical roles insulin resistance impaired glucose metabolism pathogenesis disease. This article examines implications this association, exploring potential new avenues for treatment preventive strategies AD. Key evidence linking to emphasizes metabolic processes contribute neurodegeneration, including inflammation, oxidative stress, alterations signaling pathways. By framing within context, we can enhance our understanding its etiology, which turn may influence early diagnosis, plans, measures. Understanding manifestation opens up possibility employing therapeutic incorporate lifestyle modifications use antidiabetic medications mitigate cognitive decline. integrated approach improve patient outcomes deepen comprehension intricate relationship between neurodegenerative diseases disorders.

Language: Английский

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Synergistic impact of CAG intermediate alleles in theHTTgene and microRNA dysregulation exacerbates spliceosome impairment and accelerates Tau pathology in the caudate nucleus of late-onset Alzheimer’s disease

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 19, 2025

Abstract Background Late-onset Alzheimer’s disease (LOAD) accounts for more than 95% of AD cases. Previously, we have described that 6% patients present CAG intermediate alleles in the huntingtin gene ( HTT IA s). The caudate nucleus, most affected region Huntington’s disease, is highly sensitive to these expansions, as they can induce epigenetic changes, including altered microRNA profiles. All this implies a potential source expression deregulation, affecting onset and/or progression LOAD with IAs . Methods We genotyped repeats and Apolipoprotein E APOE ) postmortem brain frozen samples from 323 335 healthy controls. From them, selected carrier non-carrier controls, neuropathological study, performed next-generation sequencing, silico target prediction pathway analysis, followed by molecular histopathological studies. Results Our study revealed presence decreases survival after onset. MicroRNA profiles nucleus are all compared control cases but pronounced carriers. In analysis suggests microRNAs expressed differentially carriers regulate key components spliceosome, splicing factors SRSF family or nuclear FUS-SFPQ complex, which was confirmed different techniques. This leads an increase Tau 3R protein, conducting higher ghost tangles, last state neurofibrillary addition, also number HTT-positive neurons repeat expansion-dependent manner. Conclusions findings demonstrate synergistic effect miRNAs deregulation evolution tau pathology, could be related accelerated misprocessing subsequent aggregation isoform, favoring faster progression. incorporation genetic screening into clinical practice would allow accurate classification patients, facilitating design personalized therapeutic interventions improving prospects management debilitating disease.

Language: Английский

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The tau isoform 1N4R confers vulnerability of MAPT knockout human iPSC‐derived neurons to amyloid beta and phosphorylated tau‐induced neuronal dysfunction

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 28, 2025

Abstract INTRODUCTION Human tau protein, composed of six brain‐specific isoforms, is a major driver Alzheimer's disease (AD). The role its isoforms however remains unclear and human AD models are scarce. METHODS We generated MAPT – (tau–) knockout (KO) induced pluripotent stem cells (iPSC) using CRISPR/Cas9, differentiated these into glutamatergic neurons, assessed isoform‐specific functions in neurons. used omic‐ approaches, live‐cell imaging, subcompartmental analysis, lentivirus‐based reintroduction specific to investigate isoform‐mediated neuronal dysfunction an model. RESULTS Tau KO iPSC‐derived neurons showed decreased neurite outgrowth axon initial segment length and, notably, resisted amyloid beta oligomer (AβO)–induced activity reduction. Introducing the 1N4R‐tau isoform, but not other confers AβO vulnerability increases KxGS phosphorylation tau, without altering or microtubule modifications. DISCUSSION While impacts development activity, tau‐KO also resistance against insult. likely mediates AβO‐induced phosphorylated toxicity, representing novel prime therapeutic target for AD. Highlights alters growth formation show differential axonal localization depletion protects (AβO)–mediated neurotoxicity. 1N4R toxicity

Language: Английский

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Phosphorylation-Induced Self-Coacervation versus RNA-Assisted Complex Coacervation of Tau Proteins

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

In this study, the role of phosphorylation in liquid–liquid phase separation (LLPS) tau, underlying driving forces, and potential implications on protein conformation subsequent aggregation were investigated. We compared vivo-produced phosphorylated tau (p-tau) nonphosphorylated under different coacervation conditions without adding crowding agents. Our findings revealed that spontaneous occurs exclusively p-tau, triggered by a temperature shift from 4 °C to room temperature, is driven electrostatic hydrophobic interactions. The p-tau self-acervation reversible with changes. Native mass spectrometry detects only two nine phosphate groups per molecule, highlighting impact tau's structural flexibility. Cross-linking showed fewer long-range contacts suggesting looser induced phosphorylation. Phosphorylation-induced LLPS RNA-induced occurred at timeframes. However, neither nor formed fibrils addition dextran sulfate or RNA as inducers. Using human kidney epithelial cells expressing R domain fused fluorescent proteins reporter cells, we observed aggregates nuclear envelope (NE) treated LLPS-state which correlates NE occurrences reported Alzheimer's disease brain sections. These provide deeper insights into through an intermediate condensation phase, offering novel perspectives neurodegenerative mechanisms.

Language: Английский

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Alzheimer’s disease and related dementias diagnosis: a biomarkers meta-analysis of general and CNS extracellular vesicles

Published: March 12, 2025

Abstract Accurate differential diagnosis of Alzheimer’s disease (AD) and related dementias (ADRD) continues to challenge neurologists. Extracellular vesicles (EVs) have emerged as a popular tool for their capacity encapsulate disease-specific signatures, particularly in neurodegenerative neurological disorders. We performed PRISMA-guided systematic review meta-analysis, utilizing sophisticated statistical modeling evaluate the diagnostic accuracy, variance, heterogeneity ( I 2 ), publication bias using biomarkers derived from general EVs n = 44) or speculative CNS-enriched 18). Biomarkers demonstrated superior less heterogeneity, than those EVs. The accuracy was low differentiating among different dementia disorders negative controls. However, analysis distinguishing AD vascular cognitive impairment achieved highest accuracy. Meta-regressions revealed importance several preanalytical factors methods. Lastly, we highlight important guidelines future studies take into consideration.

Language: Английский

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The microcirculation, the blood-brain barrier and the neurovascular unit in health and Alzheimer’s Disease. The aberrant pericyte is a central player.

Pharmacological Reviews, Journal Year: 2025, Volume and Issue: 77(3), P. 100052 - 100052

Published: March 13, 2025

High fidelity neuronal signaling is enabled by a stable local microenvironment. A high degree of homeostatic regulation the brain microenvironment, and its separation from variable potentially neurotoxic contents blood, brought about central nervous system barriers. Evidence clinical preclinical studies implicates microcirculation, cerebral hypoperfusion, blood-brain barrier dysfunction, reduced amyloid clearance in Alzheimer pathophysiology. Studying this dysregulation key to understanding disease (AD), identifying drug targets, developing treatment strategies, improving prescribing vulnerable population. This review has 2 parts: part 1 describes blood flow, extracellular fluid drainage, neurovascular unit components with an emphasis on barrier, summarizes how each aspect altered AD. Discussing structures separately allows us conclude that aberrant pericytes are early contributor AD Pericytes have multiple functions including maintenance integrity control capillary stalling, coupling, intramural periarterial glia-lymphatic (glymphatic) consequently tau clearance. vasoactive, express cholinergic adrenergic receptors, exhibit apolipoprotein E isoform-specific transport pathways. Hypoperfusion linked pericyte-mediated response. Deficient endothelial cell-pericyte (PDGBB-PDGFRβ) loops cause pericyte which contributes even initiates degeneration. We pathophysiology, interesting therapeutic target AD, emerging role regenerative therapy. SIGNIFICANCE STATEMENT: Dysregulation dysfunction circulation (including cerebrospinal fluid, interstitial fluid) occurs disease. player pericyte. fundamental implications pathophysiology development therapies.

Language: Английский

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In Situ Labeling of Pathogenic Tau Using Photo-Affinity Chemical Probes

ACS Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

Tau aggregation plays a crucial role in the development of Alzheimer's disease (AD). Developing specific techniques that can isolate pathogenic tau from brain tissue is important for understanding tauopathies and advancing targeted therapies. Here, we develop photoaffinity small molecular probes novel method situ labeling investigate their activity interacting with cells AD patient brains. Based on reported chemical structures PET tracers, designed synthesized two tau-specific probes, namely, Tau-2 Tau-4. After validation cell, mouse model, samples, our photolabeling results suggested effectively labels soluble cell models, while Tau-4 selectively binds high-molecular-weight aggregates late-stage tissues. Proteomic analysis verified isolation samples. Collectively, these findings underscore potential as powerful tools investigating proteins neurofibrillary tangles neurodegenerative diseases.

Language: Английский

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Exploring the origins of frequent tau-PET signal in vermal and adjacent regions

European Journal of Nuclear Medicine and Molecular Imaging, Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

Abstract Purpose Off-target binding remains a significant challenge in tau-PET neuroimaging. While off-targets including monoamine oxidase enzymes and neuromelanin-containing cells have been identified, recent studies indicated relevant of novel tau tracers to melanin-containing structures. To date, little is known about the effect melanocytes meninges on tracer signals brain PET data. Thus, we aimed identify target structure causal for frequently observed [ 18 F]PI-2620 signal vermis adjacent cerebellar regions. Methods 274 participants underwent dynamic tau-PET: 3/4R-tauopathies (n = 85), 4R-tauopathies 147), tau-negative disease controls 24), healthy 18). Standardized uptake value ratio (SUVR) kinetic parameters distribution volume (DVR), clearance (k2) relative perfusion (R1), were compared among cohorts sexes using Automated Anatomical Labelling (AAL) atlas. Age p-Tau levels cerebrospinal fluid (CSF) assessed their relationship with vermal signal. Furthermore, combined autoradiographic histochemical experiments post-mortem tissue deceased patients 9). Results Male revealed higher mean DVR (0.95 ± 0.13; vs. females 0.88 0.10, p < 0.0001). Sex-related differences most pronounced 3/4R-tauopathy cohort (p Mean SUVR Ver/Cbl , k2 correlation analyses did not differ groups. Histological assessments co-localization leptomeningeal pigmented strong autoradiography spots within fissures. Tau-related signals, age or correlate significantly signals. Iron deposits cause vermis. Conclusion Leptomeningeal are primary anterior vermis, whereas iron do contribute significantly.

Language: Английский

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Shapeshifter W-Tau Peptide Inhibits Tau Aggregation and Disintegrates Paired Helical Filaments

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 26, 2025

Tauopathies comprise a range of neurodegenerative conditions characterized by the aberrant accumulation tau protein clumps in brain. These aggregates are formed different splicing isoforms. Here, we analyzed role specific intron-derived peptide called W-Tau on polymerization–depolymerization filaments. This originates from new isoform protein, named W-Tau, which is due to retention intron 12. AlphaFold3 (AF3)-based silico investigations suggested that interacts with monomers. Our vitro experiments confirmed these predictions and showed inhibited aggregation. In addition, disrupted preexisting paired helical filaments (PHFs) isolated postmortem brain samples patients Alzheimer's disease, thereby supporting its potential therapeutic value. The effectiveness was demonstrated decrease aggregation observed after cotransfection PHF seeds, as analysis involving fluorescence resonance energy transfer (FRET) cell biosensor. breaks PHFs selectively attaching their ends, causing structures unwind convert into circle-like formations. Considering neuroprotective effects against tauopathies, interesting candidates for future interventions.

Language: Английский

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