Primary Cilia-Mediated Regulation of Microglial Secretion in Alzheimer's Disease

Proteomic approaches revealed that primary cilia, small hair-like structures found on cells, played a role in the regulation of microglial secretory function. Notably, primary cilia were transiently observed in less than 10% of microglia, and their presence was significantly reduced in microglia from Alzheimer's disease (AD) mice. We observed significant changes in the expression and distribution of secretomes after inhibiting the primary cilia gene intraflagellar transport particle 88 (Ift88) in microglia. Intriguingly, inhibiting primary cilia in the SEM of AD mice resulted in the expansion of extracellular amyloid plaques and damage to adjacent neurites. These results indicate that DAM-like microglia are present in the septumLS, a critical target region for hippocampal nerve bundles, and that the primary ciliary signaling system regulates microglial secretion, affecting extracellular proteostasis. Age-related primary ciliopathy probably contributes to the selective sensitivity of microglia, thereby exacerbating AD. To elucidate the dynamic changes in microglial proteomics resulting from silenced Ift88 and Aβ treatment, we performed an analysis of BV2 cell lysates and extracellular vesicles (EVs) by downregulating Ift88 expression. To investigate the specific proteomic alterations in EVs associated with CD63 and CD81, we conducted a proteomic characterization of CD63- or CD81-bound EVs in the lysate and EVs secreted from BV2 cells transfected with siIft88 and treated with Aβ, utilizing co-immunoprecipitation (Co-IP) with anti-CD63 or anti-CD81 antibodies.