Sporadic or late-onset Alzheimer's disease (LOAD) accounts for more than 95% of AD cases without any family history. Although genome-wide association studies (GWAS) have identified associated risk genes and loci for LOAD, numerous studies suggest that many adverse environmental factors, such as social isolation, are associated with an increased risk of dementia. However, the underlying mechanisms of social isolation in AD progression remain elusive. In the current study, we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice. We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 DG-enriched miRNAs, which simultaneously target reticulon 3 (RTN3), an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fiber boutons (MFBs) by recruiting multiple mitochondrial and vesicle-related proteins. Interestingly, the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation, which in turn further elevates RTN3 and forms a vicious cycle. Finally, using an artificial intelligence (AI)-assisted molecular docking approach, we determined that senktide, a selective agonist of neurokinin3 receptors (NK3R), could reduce the binding of RTN3 with its partners. Moreover, application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice. Taken together, our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.

中文翻译：

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Senktide 阻断异常的 RTN3 相互作用组，以延缓社会隔离的阿尔茨海默病小鼠的记忆衰退和 tau 病理学。

散发性或迟发性阿尔茨海默病 (LOAD) 占无任何家族史的 AD 病例的 95% 以上。尽管全基因组关联研究 (GWAS) 已经确定了 LOAD 的相关风险基因和基因座，但大量研究表明，许多不利的环境因素（例如社会隔离）与痴呆风险增加有关。然而，AD 进展过程中社会隔离的潜在机制仍然难以捉摸。在当前的研究中，我们发现 7 天的社交隔离可能会引发 AD 小鼠的模式分离障碍和苔藓纤维 CA3 回路的突触前异常。我们还发现，社会隔离破坏了组蛋白乙酰化，导致 2 个富含 DG 的 miRNA 下调，这些 miRNA 同时靶向网状蛋白 3 (RTN3)，这是一种内质网蛋白，在突触前区域聚集，干扰功能性苔藓纤维束 (MFB) 的形成）通过招募多种线粒体和囊泡相关蛋白。有趣的是，RTN3的聚集还会招募PP2A B亚基来抑制PP2A活性并诱导tau蛋白过度磷酸化，从而进一步升高RTN3并形成恶性循环。最后，利用人工智能（AI）辅助的分子对接方法，我们确定神经激肽3受体（NK3R）的选择性激动剂senktide可以减少RTN3与其伴侣的结合。此外，senktide的体内应用有效地恢复了社交孤立的AD小鼠的DG回路紊乱。总而言之，我们的研究结果不仅证明了由社会隔离和 tau 病理学精心策划的苔藓纤维突触疾病背后的表观遗传调控机制，而且还揭示了 AD 的一种新的潜在治疗策略。