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

Many pathological alterations happen decades before cognitive decline in Alzheimer’s 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.