A novel PIAS1-GSK3β signaling axis in tauopathy and a cell-permeable blocking peptide designed to disrupt the PIAS1-GSK3β interaction are uncovered and provide a promising targeted therapeutic strategy for Alzheimer's disease.
Findings support a model in which tau dysfunction results from the convergence of molecular aberrations and genetic susceptibility within a pathological network involving amyloid-β, neuroinflammation, and synaptic failure.
S. Sura, S. Jagadeesan, M. A. M. Moklas et al.· Molecular Biology Reports· 0 citations
Alzheimer's disease (AD) is a neurodegenerative disorder with significant sex-related differences, exhibiting a higher incidence rate in elderly women. Tau pathology has been implicated in sex-associated differences in AD susceptibility and disease progression, contributing to differential pathological burden between males and females. Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi) used in cancer treatment, has shown potential therapeutic effects in various neurological and psychiatric disorders; however, the mechanisms underlying its regulation of tau-associated pathology remain poorly understood, with limited evidence regarding its effects in tau-related neurodegenerative conditions. In this study, we investigated the effects of SAHA treatment on an AAV-P301L-Tau-induced tauopathy model. In vivo, we observed that SAHA administration significantly improved p-Tau levels in the hippocampus and cortex of mice, reduced microglial activation and neuronal damage, and alleviated tauopathy-associated cognitive impairments. Our findings revealed sex-associated differences in Tau-related pathological alterations, with female mice exhibiting greater pathological changes and differential responses to SAHA treatment in several molecular and histological indicators. Further combined in vivo and in vitro experiments revealed that SAHA was associated with modulation of the PI3K/AKT/GSK3β signaling pathway, suppression of NF-κB activation, and attenuation of neuroinflammatory responses, including reductions in experimentally measured inflammatory markers such as interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α). These molecular alterations may represent important regulatory components contributing to the neuroprotective effects of SAHA, rather than acting as the sole determinants of its therapeutic efficacy. In summary, these results indicate that SAHA can improve Tau-associated pathological alterations in an AAV-P301L-Tau-induced tauopathy model. The potential mechanisms may involve coordinated regulation of multiple pathological processes, including modulation of Tau phosphorylation, neuroinflammatory responses, and aging-associated signaling pathways. The observed sex-dependent responses to SAHA provide additional insights into the potential influence of biological sex on HDACi-based therapeutic strategies, although the molecular mechanisms underlying these differences require further investigation.
Zhidan Shi, Xinyi Cheng, Chu Zhang et al.· International Immunopharmaco...· 0 citations
Alzheimer’s disease (AD) represents the most prevalent neurodegenerative disorder worldwide,
characterized by progressive cognitive decline, amyloid-beta (Aβ) plaque deposition, and neurofibrillary
tangle formation. While the amyloid cascade and tau propagation hypotheses have dominated the field for
decades, emerging evidence implicates epigenetic mechanisms, particularly PIWI-interacting RNAs
(piRNAs), in the early pathogenesis of sporadic AD. This review synthesizes current knowledge regarding
piRNA dysregulation in AD, examining mechanistic links between piRNA loss, transposable element
activation, Aβ toxicity, and tau pathology while evaluating therapeutic implications. We first discuss how ADassociated stressors, including oxidative stress and mitochondrial dysfunction, alter piRNA expression
profiles in vulnerable brain regions such as the hippocampus and cortex. Next, we examine mechanistic
convergence points: aberrant piRNAs may de-repress transposable elements (e.g., LINE-1), triggering
cytosolic DNA sensing pathways and neuroinflammation that exacerbate Aβ aggregation. Simultaneously,
piRNA imbalance is hypothesized to disrupt post-transcriptional networks governing microtubule-associated
protein tau, potentially via competitive binding with microRNAs or through PIWI-clade proteins that directly
interact with tau kinases (e.g., GSK-3β, CDK5). Additionally, we evaluate evidence linking piRNA-mediated
epigenetic modulation of BACE1 and MAPT promoters to sustained amyloidogenic and tauogenic cascades.
Key databases including PubMed, Google Scholar, and Europe PMC were searched for relevant publications
from 2017–2026. Multiple studies demonstrate significant piRNA dysregulation in human AD brains and
cerebrospinal fluid, with specific piRNA signatures correlating with Braak staging and amyloid/tau PET
biomarkers. Mechanistically, Aβ-induced oxidative stress disrupts PIWI protein expression, leading to LINE-1
retrotransposon derepression, genomic instability, and feedforward amplification of amyloidogenic
processing. Tau pathology further exacerbates piRNA depletion through PIWI-piRNA complex
mislocalization, creating a vicious cycle of epigenetic dysregulation and neurodegeneration. piRNA
dysregulation represents a convergent node linking Aβ and tau pathologies with downstream
neuroinflammation via cGAS-STING activation. Restoring piRNA function through synthetic mimics, PIWI
stabilizers, or CRISPR activation of piRNA clusters offers novel therapeutic avenues for disease modification
in AD.
S. Taherkhani, Zeynab Sharifiaghdam, Parnian Amani· SVOA Neurology· 0 citations
BackgroundAbnormal tau hyperphosphorylation is a central feature of Alzheimer's disease (AD). Tau tubulin kinase 1 (TTBK1) is a key kinase involved in tau phosphorylation, but its upstream regulatory mechanisms remain poorly understood.ObjectiveTo identify circRNAs involved in the upstream regulation of TTBK1 and elucidate their molecular mechanisms and functional roles in tau hyperphosphorylation and cognitive impairment in AD.MethodsHippocampal circRNA and miRNA profiles were analyzed in 6-month-old 3×Tg-AD and wild-type mice. The candidate regulatory axis was investigated using qRT-PCR, Western blotting, dual-luciferase reporter and RNA immunoprecipitation assays, cell viability and apoptosis analyses, lentiviral intervention, immunofluorescence, silver staining, and behavioral tests.ResultsCirc_0004801 was upregulated and miR-7688-5p was downregulated in the hippocampus of 3×Tg-AD mice. Circ_0004801 knockdown enhanced HT22 cell viability, reduced apoptosis, decreased TTBK1 expression, and suppressed tau phosphorylation at Ser199, Ser202, and Ser396. MiR-7688-5p overexpression reduced TTBK1 expression and tau phosphorylation at Ser199 and Ser202, whereas TTBK1 overexpression reversed these effects. Reporter and RNA immunoprecipitation assays supported a sequence-dependent interaction between circ_0004801 and miR-7688-5p and their association with the Ago2 complex. In vivo, circ_0004801 knockdown reduced hippocampal p-tau (Ser199) and improved spatial learning, memory, and object recognition, whereas TTBK1 overexpression attenuated these benefits.ConclusionsCirc_0004801 acts as an upstream regulator of TTBK1 by sequestering miR-7688-5p, thereby promoting tau hyperphosphorylation and cognitive impairment in AD. This axis may represent a potential target for tau-directed intervention.
Qing-Qing Li, Jie Xiao, Guo-Rong Deng et al.· Journal of Alzheimer's Disea...· 0 citations
A new Drosophila tauopathy model expressing eGFP-tagged human TauWT or the disease-associated TauP301L variant in the nervous system is established and 5-HT7R signaling is identified as a conserved and druggable modifier of Tau toxicity.
Mariana I. Tsap, Valeriya V. Navrotska, J. Labus et al.· bioRxiv· 0 citations
Alzheimer's disease (AD) is the most dominant form of dementia characterized by neurodegeneration which leads to progressive cognitive decline and memory loss, the common symptoms of AD. While amyloid-β peptide accumulation has traditionally been the primary focus of AD research, there is growing evidence that tau pathology also contributes significantly in disease progression. Tau is a microtubule-associated protein that normally stabilizes microtubules and supports axonal transport within neurons. However, abnormal hyperphosphorylation causes tau to detach from microtubules, misfold and aggregate into toxic filaments which ultimately lead to neurodegeneration and eventually cell death. This paper reviews the structure of tau protein, its physiological and pathological behaviours and tau's mechanism in terms of disease progression. This paper also examines clinical and preclinical evidences and discusses the efficacy and limitations of three tau-targeted therapeutic approaches: gosuranemab, a monoclonal antibody designed to prevent the spread of extracellular tau; BIIB080, an antisense oligonucleotide that reduces tau production by targeting MAPT mRNA; and leucomethylthioninium bis (LMTM), a tau aggregation inhibitor. Studies also suggest the potential of combination therapies targeting multiple pathological pathways to enhance efficacy. Though no tau-targeted therapy has yet to demonstrate definitive clinical benefit, continued research supports tau as an important therapeutic target and contributes to the development of more effective treatments for AD.
Zhuo-Yu Wang· MedScien· 0 citations
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