时间标签：数据日期 2026-10-31 · 生成时间 2026-11-01 05:30（Asia/Shanghai）｜ 检索窗口 PubMed edat 2026/10/28–2026/10/31 ｜ 情报发生日期 2026-10-31
研究问题
Accumulation of pathological Tau in the human brain is implicated in a broad spectrum of neurodegenerative diseases collectively termed tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration and frontotemporal dementia., , Under physiological conditions, Tau stabilizes microtubules and supports axonal transport; however, abnormal post‐translational modifications reduce its microtubule‐binding affinity and promote its redistribution, misfolding and aggregation., , The dissociation of phosphorylated Tau (p‐Tau) from microtubules consequently disrupts neuronal integrity and contributes to synaptic dysfunction and cognitive decline.；Current strategies mainly focus on blocking extracellular Tau propagation or promoting the clearance of intracellular pathological Tau, including monoclonal antibodies, TRIM‐based protein quality‐control s
方法
The assay was repeated five times for each group, with a 2‐minute rest period between successive trials.；These cells were then tested by Western blotting and used in this study.；The following strains of mice were used in this study: wild‐type (WT) C57BL/6J; rTg4510 mice (Strain#:024854, RRID: IMSR_JAX:024854); Thy1‐Cre (Jackson Laboratory, Strain#:012708, RRID: IMSR_JAX:012708); Arrdc4fl/fl (GemPharmatech, Strain NO.；All the experimental processes and research conform to the Institute of Developmental Biology and Molecular Medicine (IDM) ethics program, policies, and guidelines.
核心结论
These models included (1) classic AD models driven by AβArc or Aβ42 overexpression, or induced by OA; (2) neuroinflammatory models induced by lipopolysaccharide (LPS) or Arf1 deletion; and (3) supplementary neurodegenerative disease models, including Parkinson's disease models carrying pathogenic Park or Gba1b mutations and an amyotrophic lateral sclerosis model expressing TDP‐43Q331K (Figure ).；Notably, ARRDC4 was the only α‐arrestin family member that was consistently increased at both mRNA and protein levels in drug‐induced SH‐SY5Y and Neuro‐2a AD model cells (Figures and ).；Together, these results identify ARRDC4 as a candidate α‐arrestin regulator consistently associated with AD‐relevant pathology in both human brain datasets and neuronal disease models. ‖ 结论：These findings reveal a previously unrecognized ARRDC4–USP14–Tau axis and support ARRDC4 as a potential therapeutic target for Tau‐associated neurodegeneration.
局限
First, although ARRDC4 overexpression was useful for defining molecular mechanisms, supraphysiological ARRDC4 levels may not fully recapitulate endogenous disease states.；Future studies using endogenous ARRDC4 perturbation and disease‐relevant human neuronal systems will be important for refining this mechanism under more physiological conditions.
对本项目的价值
★★☆☆☆ 脑老化是最大未满足需求，也是终点最难量化的领域；biomarker 与认知读数选择最敏感。
全文来源
PMC JATS 全文（正文 69,956 字符，已过标题/DOI 逐字归属校验）
原文题录
- 英文标题：ARRDC4 drives Tau pathology via USP14-mediated deubiquitination and acts as a novel therapeutic target in Alzheimer's disease.
- 期刊与标识：Alzheimers Dement · PMID 42957973 · DOI 10.1002/alz.71926
A 级证据分级：A 级（同行评议人体研究）
本文属人体研究证据，但需注意：观察性或小样本干预的结论不等于已证实临床获益；效应量与长期安全性仍需更大规模、更长随访的试验验证。
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