Changes in the primary cilia in Alzheimers disease early development is associated with alterations in the axon initial segment.

Many pathological alterations happen decades before cognitive decline in Alzheimers disease (AD) patients. Identifying the earliest changes in AD neurons is crucial for AD diagnosis and therapy development targeting upstream events in AD pathogenesis. Here, we demonstrated the early common alterations in the hippocampal neurons from 3 familial AD mouse lines (APP/PS1, 5FAD, 3*Tg) are associated with the primary cilium morphology and ciliary GPCRs. The primary cilia interact with the axon initial segment (AIS) through ciliary GPCR signaling and transcriptional regulation of AIS mater organizer protein AnkG. Our results provide new insights for AD pathogenesis especially during early stage, and a novel mechanism by which ciliary signaling may modulate neuronal activity through regulating the structure and plasticity of the AIS. Understanding AD development at early stage could help identifying new potential targets for AD prevention and therapy. To investigate the specific function of SSTR3 in early AD, we used wild-type mice and SSTR3-knocked out mice. Then we conducted RNA sequencing analysis using the hippocampal tissues from the two types of mice to compare gene expression.阿尔茨海默病（Alzheimer's Disease, AD）患者在出现认知功能减退数十年前，便已存在多种病理异常。精准识别AD神经元的早期变化，对于AD诊断以及靶向AD发病机制上游事件的治疗研发至关重要。本研究证实，3种家族性AD小鼠模型（APP/PS1、5FAD、3*Tg）的海马神经元早期共通病理改变，与初级纤毛形态及纤毛G蛋白偶联受体（GPCR）密切相关。初级纤毛可通过纤毛GPCR信号通路，以及对轴突初始段（Axon Initial Segment, AIS）核心组织者蛋白AnkG的转录调控，与轴突初始段产生相互作用。本研究结果为AD发病机制，尤其是早期阶段的发病机制提供了全新视角，并揭示了纤毛信号可通过调控轴突初始段的结构与可塑性，进而调节神经元活动的全新机制。深入阐明AD的早期发生发展过程，有助于发掘AD预防与治疗的全新潜在靶点。为探究生长抑素受体3（SSTR3）在AD早期的具体功能，本研究设置了野生型小鼠与SSTR3基因敲除小鼠两组模型，随后通过提取两组小鼠的海马组织进行RNA测序分析，以比较二者的基因表达差异。