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At least 19 recordsLinked to original sources
PubMed2026

GWAS of Tau-Neurodegeneration Mismatch Identifies New Risk Loci for Susceptibility to Tau.

BACKGROUND: In Alzheimer's disease (AD), neurodegeneration is primarily attributed to the accumulation of tau neurofibrillary tangles. However, the distribution patterns of both tau pathology and neurodegeneration vary across different brain regions and among individuals. Moreover, multiple factors may influence the relationship between tau burden and neurodegenerative processes. Identifying the genetic architecture associated with deviation in the tau-neurodegeneration relationship can provide deeper mechanistic insights and guide the development of precision medicine strategies. METHODS: Here, I perform a genome-wide association study (GWAS) of cortical tau and thickness quantified by positron emission tomography (PET) and magnetic resonance imaging (MRI) in 794 participants from two cohorts of Alzheimer's disease Neuroimaging Initiative (ADNI) and A4. RESULTS: A GWAS was identified between the Tau/Neurodegeneration residual and two novel loci on chromosomes 7 and 14, with two SNPs (rs9323573 and rs9784993) exceeding the genome-wide significance threshold (p ≤ 5 × 10-8). SNP rs9323573 is located in STXBP6 on chromosome 14, while rs9784993 is in AKAP9 on chromosome 7, both of which were directly genotyped. The minor allele G of both SNPs (rs9323573, MAF = 0.221, p = 2.60 × 10-8; rs9784993, MAF = 0.197, p = 4.92 × 10-8) was associated with lower Tau/Neurodegeneration residuals, indicating higher-than-expected neurodegeneration given tau levels. CONCLUSION: GWAS of tau-related neurodegeneration identified two novel genetic variants in the loci AKAP9 and STXBP6 leading to higher than expected regional neurodegeneration given the tau level. Identifying genetic factors involved in tau-neurodegeneration mismatch may improve our understanding regarding the potential mechanistic downstream leading to susceptibility or resilience to tau pathology.

Humans↗
PubMed2026

A third-generation, high-affinity biparatopic anti-tau antibody inhibits intracellular tau aggregation seeded by Alzheimer's brain extracts.

BACKGROUND: Tau immunotherapy has recently shown clinical promise but required high dosing. We developed NIDB-3101, a novel third-generation, high-affinity anti-tau biparatopic antibody designed for superior tau binding, aggregation inhibition, and extended half-life. METHODS: NIDB-3101 binds tau's microtubule-binding region and C-terminal domains. Various binding and cellular functional assays using recombinants, but more importantly human AD extracts were used to assess NIDB-3101 benefits. Half-life mutations impact was assessed via FcRn binding and cellular assays recycling. RESULTS: NIDB-3101 exhibited sub-nanomolar affinity, binding a broad spectrum of pathological tau species in AD homogenates, inhibited AD extracts-induced cellular effect compared to benchmark antibodies. Mutations enhanced hFcRn-mediated cellular recycling. CONCLUSIONS: NIDB-3101 captures a broad spectrum of pathological tau species leading to strong cellular efficacy using human AD extracts, supporting further clinical development as a potential disease-modifying therapy for AD and related tauopathies.

tau Proteins↗
PubMed2025

Multi-omic phenotyping of iPSC-derived neurons harboring the MAPT V337M mutation reveals tau hypophosphorylation and perturbed axon morphology pathways.

Tau aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia. There are disease-causing variants of the tau-encoding gene, MAPT, and the presence of tau aggregates is highly correlated with disease progression. However, the molecular mechanisms linking pathological tau to neuronal dysfunction are not well understood. This is in part due to an incomplete understanding of the normal functions of tau in development and aging, and how the associated molecular and cellular processes change in the context of causal disease variants of tau. To address these questions in an unbiased manner, we conducted multi-omic characterization of iPSC-derived neurons harboring the MAPT V337M mutation or MAPT knockdown. RNA-seq and phosphoproteomics revealed that both V337M mutation and tau knockdown perturbed levels of transcripts and phosphorylation of proteins related to axonogenesis or axon morphology. Surprisingly, we found that neurons with V337M tau had much lower tau phosphorylation than neurons with WT tau. Functional genomics screens uncovered regulators of tau phosphorylation in neurons and found that factors involved in axonogenesis modified tau phosphorylation in both MAPT WT and MAPT V337M neurons. Intriguingly, the p38 MAPK pathway specifically modified tau phosphorylation in MAPT V337M neurons. We propose that V337M tau perturbs tau phosphorylation and axon morphology pathways that are relevant to the normal function of tau, which could contribute to previously reported cognitive changes in preclinical MAPT variant carriers.

Journal Article↗
PubMed2026

High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction.

The cellular uptake and propagation of tau are central features of tauopathies, including Alzheimer's disease, and are mediated by the endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1). While prior studies have implicated LRP1 in tau binding and internalization, the biochemical features of this interaction and its suitability for therapeutic targeting remain incompletely defined. Here, we establish a quantitative and scalable framework to interrogate the tau-LRP1 interaction and identify small-molecule modulators. We engineered and purified the LRP1 ligand-binding domain 4 (BD4), a key region mediating tau interaction, and developed multiple orthogonal assays, including fluorescence polarization, split luciferase complementation, and time-resolved FRET, to measure LRP1-BD4 interactions with tau and a known peptide ligand. Across assay formats, we observe consistent binding affinities in the nanomolar range and demonstrate competitive displacement by tau, receptor-associated protein (RAP), and a peptide ligand, supporting overlapping binding interfaces. Leveraging these platforms, we performed small molecule high-throughput screening and identified a set of candidate inhibitors of the LRP1-BD4-tau interaction. Selected compounds reduced tau uptake in a cellular assay, phenocopying competitive inhibition by tau and a peptide ligand. Together, these studies define the LRP1-BD4-tau interaction as a biochemically tractable and druggable interface and establish an integrated discovery pipeline linking mechanistic characterization to functional cellular outcomes. This work provides a foundation for the development of therapeutic strategies targeting LRP1-mediated tau uptake.

Journal Article↗
PubMed2026

Riboregulation: a non-canonical tau function.

Almost since its discovery, tau protein has perplexed scientists and clinicians with its varied roles in physiology as well as its appearance as phosphorylated protein aggregates of various structures in many neurodegenerative diseases. Tau plays a role in microtubule stabilization, but from the earliest of studies, tau has also been observed to bind to RNA, with recent research suggesting tau has a higher affinity for some RNA species compared to microtubules. In the context of disease, tau dysfunction potentiates disruptions to RNA metabolism, including the perturbation of mRNA splicing, impairment of translation, de-repression of transposable elements, and alteration of RNA export and degradation. Tau aggregates directly sequester diverse RNA species and RNA binding proteins. Emerging evidence reinforces the characterization of tau as an RNA binding protein, highlighting questions about both the physiological and disease-related functions of this direct RNA binding. The disparate structure of tau in normal and various disease states makes teasing apart the various impacts on RNA and regulation a more difficult puzzle requiring future study. In this review, we summarize the evidence for tau's role in RNA biology, including as an RNA binding protein.

tau Proteins↗
PubMed2026

Near-Infrared Fluorescent PROTAC Enables Theranostic Imaging and Selective Tau Degradation in Alzheimer's Disease.

The hyperphosphorylated Tau (p-Tau) protein plays a central role in the pathogenesis of Alzheimer's disease (AD) by driving neurofibrillary tangle formation and neuronal dysfunction. While proteolysis targeting chimeras (PROTACs) offer a promising approach for directly eliminating pathogenic proteins, their real-time visualization in living systems remains challenging. Here, we report the rational design and synthesis of a series of near-infrared (NIR) fluorescent Tau-targeting degraders that integrate theranostic imaging with targeted protein degradation. Among them, compound D9 emerges as a dual-functional degrader capable of both high-contrast fluorescence tracking and potent Tau clearance at 10 nM. Mechanistic investigations indicate that D9 induces Tau degradation through activation of the ubiquitin-proteasome system (UPS), as confirmed by inhibitor assays. Beyond Tau degradation, D9 also downregulates amyloid precursor protein (APP) and β-amyloid (Aβ) expression, suggesting broader neuroprotective effects. In in vivo studies, D9 significantly promotes p-Tau clearance and alleviates cognitive deficits in 3 ×Tg-AD mice. These findings demonstrate that D9 represents a first-in-class NIR fluorescent PROTAC for theranostic imaging and targeted degradation of Tau, providing a powerful platform for visualizing degradation dynamics and developing next-generation AD therapeutics.

Alzheimer's disease↗
PubMed2025

Tau uptake by human neurons depends on receptor LRP1 and kinase LRRK2.

Extracellular release and uptake of pathogenic forms of the microtubule-associated protein tau contribute to the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease. Defining the cellular mechanisms and pathways for tau entry to human neurons is essential to understanding tauopathy pathogenesis and enabling the rational design of disease-modifying therapeutics. Here, whole-genome, loss-of-function CRISPR screens in human iPSC-derived excitatory neurons, the major neuronal cell type affected in these diseases, provide insights into the different cellular pathways for uptake of extracellular monomeric and fibrillar tau. Monomeric and fibrillar tau are both taken up by human neurons by receptor-mediated endocytosis, but involve different routes of entry at the neuronal surface: the low-density lipoprotein LRP1 is the primary receptor for monomeric tau, but contributes less to fibrillar tau entry. Similarly, endocytosis of monomeric tau is dependent on the familial Parkinson's disease gene LRRK2, but not required for endocytosis of fibrillar tau. These findings implicate LRP1 and LRRK2 in the pathogenesis of tauopathies and Parkinson's disease, and identify LRRK2 as a potential therapeutic target for altering progression of these diseases.

Humans↗
PubMed2026

Diagnostic value of blood p-tau subtypes in Alzheimer's disease progression and pathology: systematic review and meta-analysis.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease and the most likely to lead to dementia. With the availability of the latest therapies, the need for Alzheimer's disease diagnosis is now gradually increasing. Whereas blood phosphorylated-tau (p-tau) has demonstrated excellent performance in the prediction and diagnosis of disease progression and A&#x3b2; positivity in AD, there are differences between different p-tau subtypes. Therefore, a pooled analysis of different blood p-tau subtypes is of more important clinical value. METHOD: Relevant literature was screened by complete search in four databases, Pubmed, Embase, Cochrane Library and Scopus. Relevant data and AUC and their confidence intervals of the included literature were extracted and analyzed by classification according to p-tau subtypes. Quality assessment was performed using the QUADAS-2 tool. RESULT: Our results reveal that p-tau217 performs better in the diagnostic performance in most stages of AD, which is consistent with the guidelines. However, our results concluded that p-tau217 has poorer diagnostic performance in the stages of cognitive unimpaired or less cognitively impaired, especially in the A&#x3b2; positivity diagnosis of SCD and CU. Head-to-head meta-analyses formally confirmed that p-tau217 significantly outperforms p-tau181 across AD dementia, A&#x3b2; positivity, tau positivity, and biological staging (all P&#x2009;<&#x2009;0.05), whereas no significant difference was observed between p-tau231 and p-tau181. CONCLUSION: By integrating single-arm pooled AUC estimates with formal head-to-head statistical comparisons, our study provides evidence-based support for plasma p-tau217 as the subtype with the most robust diagnostic performance across AD pathology and biological staging. Head-to-head analyses formally confirmed that p-tau217 significantly outperforms p-tau181 in A&#x3b2; positivity, Tau positivity, and biological staging.

Humans↗
PubMed1977

Immunoflourescent staining of cytoplasmic and spindle microtubules in mouse fibroblasts with antibody to tau protein.

tau protein isolated from porcine brain microtubules was further purified by electrophoretic elution from polyacrylamide gels and used to prepare antisera in rabbits. The antiserum to tau specifically stains mitotic spindles and a filamentous network within mouse fibroblasts when the indirect immunofluorescence technique is used. The staining of the filamentous network and mitotic spindles is identical to that observed when cells are treated with antiserum prepared against electrophoretically purified tubulin. The filamentous network observed with either serum is sensitive to Colcemid. Absorption of anti-tau serum with electrophoretically purified tubulin does not remove the immunofluorescent staining of the mitotic spindle, whereas absorption with electrophoretically purified tau protein does. Conversely, absorption of antitubulin serum with tubulin eliminates its ability to stain the mitotic spindle, whereas absorption with tau has no effect. We conclude that tau protein and tubulin are antigenically distinct proteins and that tau is an integral part of microtubules in vivo. These results also provide evidence that tau protein, or an antigenically related protein, is associated with microtubules not only in brain but also in other cell types.

Animals↗
PubMed2025

Elevated Cerebrospinal Fluid Total Tau in Niemann-Pick Disease Type C1: Correlation With Clinical Severity and Response to Therapeutic Interventions.

Niemann-Pick disease, type C1 (NPC1) is an inborn error of intracellular cholesterol transport. Impaired function of NPC1 leads to endolysosomal accumulation of unesterified cholesterol, which results in progressive neurodegeneration. Although the age of onset is variable, classical NPC1 is a pediatric disease. Identification of biomarkers that correlate with clinical phenotype and respond to therapeutic interventions will be essential for developing effective therapeutic interventions. A&#x3b2; peptides and Tau protein are primary components of amyloid plaques and neurofibrillary tangles, respectively, which are major pathological features in neurodegenerative disorders. Cerebrospinal fluid (CSF) levels of total Tau, a biomarker of axonal damage, were elevated ~3-fold (p&#x2009;<&#x2009;0.0001) in 106 individuals with Niemann-Pick disease, type C1, relative to age-appropriate comparison samples. Baseline CSF total Tau levels correlated with clinical measures of disease severity. Specifically, CSF total Tau levels decreased with increased age of neurological onset (rs&#x2009;=&#x2009;-0.42, FDR adj. p&#x2009;<&#x2009;0.0001) and increased with increased Annual Severity Increment Score (rs&#x2009;=&#x2009;0.52, FDR adj. p&#x2009;<&#x2009;0.0001). Baseline CSF total Tau levels were decreased 40% (p&#x2009;=&#x2009;0.0066) in individuals being treated with miglustat, and longitudinal analysis substantiated this observation with a 40% decrease (p&#x2009;<&#x2009;0.0001, 95% CI 32%-47.4%). Longitudinal analysis also showed a significant (p&#x2009;=&#x2009;0.004) decrease of 19% (95% CI 7%-30%) in total Tau levels associated with intrathecal 2-hydroxypropyl-&#x3b2;-cyclodextrin therapy. These data show that CSF total Tau levels are significantly increased in individuals with NPC1, positively correlated with increased disease severity, and respond to therapeutic interventions.

Humans↗
PubMed2026

Lysine methylation is an endogenous post-translational modifications of tau protein in human brain and a modulator of aggregation propensity.

Tau protein undergoes a broad range of post-translational modifications in the brain, influencing its structure, solubility, and propensity to aggregate. This chapter presents an integrated methodological framework for characterizing tau methylation and evaluating its impact on tau biology. We describe procedures for isolating soluble and filamentous tau from post-mortem human brain tissue while preserving modifications for proteomic analysis. These approaches support precise mapping of methylation sites alongside other co-occurring modifications. To model methylation under controlled conditions, we outline protocols for recombinant tau expression, purification, and chemical reductive methylation, including radiolabeled assays for determining modification stoichiometry. We then detail biophysical assays used to assess how methylation alters tau conformation and aggregation propensity. This methodological framework supports experimentation seeking insight into mechanisms relevant to Alzheimer's disease and related tauopathies.

Humans↗
PubMed2026

A proteomic analysis of the PHF-forming tau fragment (tau297-391) following uptake into differentiated human neuronal SHSY5Y cells.

Tau self-assembly and intracellular deposition are associated with a group of neurodegenerative diseases called tauopathies, which include Alzheimer's disease (AD) and Pick's disease. Here, we measured the proteome response in human neuronal cells (differentiated SH-SY5Y) following the addition of a spontaneously amyloidogenic region of tau known as dGAE (tau297-391), which forms AD-like paired helical filaments in vitro, and proteomic analysis showed increased endogenous tau expression. Further interactome analysis uncovered increased association between tau and proteins associated with nuclear chromatin, the nucleolus, and the spliceosome, as well as the thiol-peroxidase, PRDX6, alongside an increase in reactive oxygen species. The present work highlights a method to identify proteome pathways that may play an important role in the development of tau pathology and reveals an oxidative stress response to dGAE.

Humans↗
PubMed2026

Tau proteoforms as plasma biomarkers in Alzheimer's disease: mechanisms, measurement, and medicine.

INTRODUCTION: Blood-based tau proteoforms have emerged as specific, scalable biomarkers of Alzheimer's pathology, addressing the limitations of symptom-based diagnosis, neuroimaging, and invasive cerebrospinal fluid (CSF) testing. This review synthesizes advances in tau phosphorylation and truncation biology, evaluates translation from CSF to plasma with state-of-the-art proteomics, and outlines the analytical standards and cross-matrix calibration needed for clinical adoption. AREAS COVERED: We conducted a literature search in PubMed and Google Scholar. We reviewed studies published between January 2005 and September 2025 investigating tau proteoforms in Alzheimer's disease. EXPERT OPINION: Blood-based tau proteoforms are poised to move Alzheimer's diagnostics from specialized imaging to accessible frontline testing, with plasma p-tau217 approaching positron emission tomography (PET) and CSF performance and multi-analyte panels with glial fibrillary acidic protein (GFAP) or neurofilament light (NfL) improving differential diagnosis while reducing invasiveness and cost. Building on the first FDA-cleared plasma assay (Lumipulse G p-tau217/A&#x3b2;1-42 Ratio) in May 2025, we anticipate a dual pathway over the next decade in which referral centers use high-plex mass spectrometry (MS) panels for phosphoforms and truncations, while primary care adopts automated high-throughput immunoassays (e.g. chemiluminescent enzyme immunoassay (CLEIA)) for triage, supported by harmonized standard operating procedures (SOPs), cross-matrix calibration, and robust reference materials.

Humans↗
PubMed2026

Priming of CD8+ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration.

Alzheimer's disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8+ T cells correlating with tau pathology severity. However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear. In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8+ T cells into effector cells. We show that tauopathy mice lacking cDC1s or antigen cross-presentation are protected from neurodegeneration, with reduced brain CD8+ T cell infiltration and glial activation. The remaining CD8+ T cells exhibit limited clonal expansion, consistent with impaired priming. We further demonstrate that brain-derived antigens are presented in secondary lymphoid tissues, suggesting a site of T cell activation. Together, these findings establish cDC1-dependent peripheral priming as a key driver of CD8+ T cell accumulation in the brain and tau-mediated neurodegeneration.

Journal Article↗
PubMed1979

Effect of glucocorticoid administration on the rate of muscle protein breakdown in vivo in rats, as measured by urinary excretion of N tau-methylhistidine.

The role of glucocorticoids in regulating the rate of muscle protein breakdown was evaluated by measuring excretion of N(tau)-methylhistidine during administration of various doses of corticosterone to adrenalectomized rats. Groups of rats received daily subcutaneous injections of 0, 0.2, 0.5, 1.0, 5.0 or 10.0mg of corticosterone/day per 100g body wt. for 7 days, followed by 3 days without hormone treatment, after which they were killed. A group with intact adrenal glands served as an additional control. All animals were pair-fed with the untreated adrenalectomized group. No significant differences were noted in growth rate or N(tau)-methylhistidine excretion between the intact or adrenalectomized control groups, or those given 0.2, 0.5 and 1.0mg of corticosterone, whereas growth ceased and N(tau)-methylhistidine excretion rose markedly in the groups receiving 5 and 10mg of corticosterone. After these two high doses of corticosterone, but not after lower doses, there was a loss of weight of the gastrocnemius muscle per 100g of final body wt., but not of the soleus and extensor digitorum longus muscles. The two highest doses of corticosterone also resulted in an increase in liver weight per 100g of final body wt. Lower doses of corticosterone did not cause these changes. Plasma corticosterone concentrations, measured on the final day of injection and again at the time of killing, were decreased to near zero by adrenalectomy and were little raised by doses of 0.2 and 0.5mg daily, but were increased to within the normal range by the 1mg dose. At 5 and 10mg doses, plasma corticosterone concentrations were sustained at 2-3 times those of intact rats, and thus in the range reported for rats exposed to severe stress. Rats given 5 and 10mg doses of corticosterone had glycosuria, and showed considerably elevated concentrations of insulin in the plasma. It is concluded that plasma concentrations of glucocorticoids within the normal range do not regulate the rate of muscle protein breakdown, whereas excessive plasma concentrations of corticosteroids, equivalent to those observed in severe stress, can accelerate muscle protein breakdown.

Adrenalectomy↗
PubMed1979

Differences in surface morphology of microtubules reconstituted from pure brain tubulin using two different microtubule-associated proteins: the high molecular weight MAP 2 proteins and tau proteins.

Microtubules were reconstituted from homogeneous brain tubulin and homogeneous preparations of two different microtubule associated proteins, the high molecular weight MAP 2 proteins or the tau proteins. The resulting microtubules were characterized by three electron microscopical procedures: Thin sectional analysis of embeded material, negative staining analysis using a STEM microscope and high resolution metal-shadowing analysis. By all three procedures MAP 2 microtubules have a much rougher surface morphology than tau microtubules, in agreement with the much higher molecular weight of the MAP 2 proteins. Tau microtubules, however, do not show the very smooth surface of microtubules assembled from pure tubulin in the absence of any microtubule associated proteins. In the case of MAP 2 microtubules thin sectional analysis as well as metal shadowing reveals that the globular protrusions seen in negative staining analysis appear as linear side arms which may extend by as much as 30 nm on both sides from the microtubular wall proper, giving rise to an overall structure with a diameter close to 100 nm. The possible implication of such structures for in vivo situations is briefly discussed as is the possibility that the "halo-effect" around microtubules seen in vivo may be due to a structural organization similar to that of MAP 2 tubules in vitro.

Animals↗