Primary cilia-mediated regulation of microglial secretion in Alzheimer’s disease

Frontiers in Molecular Biosciences

Molecular Biosciences

Hyeyoung Lee¹  Seungun Yeo²  Hyun Jin Jung²  Youngshik Choe²  Jaemyung Jang² 

[1]Division of Applied Bioengineering, Dong-eui University, Busan, Republic of Korea

[2]Korea Brain Research Institute, Daegu, Republic of Korea

关键词: microglia;    primary cilia;    extracellular vesicles;    amyloid-beta;    Alzheimer’s disease;   

DOI  :  10.3389/fmolb.2023.1250335

 received in 2023-06-30, accepted in 2023-09-28,  发布年份 2023

来源: Frontiers

【 摘 要 】

Alzheimer’s disease (AD) is a brain disorder manifested by a gradual decline in cognitive function due to the accumulation of extracellular amyloid plaques, disruptions in neuronal substance transport, and the degeneration of neurons. In affected neurons, incomplete clearance of toxic proteins by neighboring microglia leads to irreversible brain inflammation, for which cellular signaling is poorly understood. Through single-cell transcriptomic analysis, we discovered distinct regional differences in the ability of microglia to clear damaged neurites. Specifically, microglia in the septal region of wild type mice exhibited a transcriptomic signature resembling disease-associated microglia (DAM). These lateral septum (LS)-enriched microglia were associated with dense axonal bundles originating from the hippocampus. Further transcriptomic and 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 microglia, and their presence was significantly reduced in microglia from AD mice. We observed significant changes in the secretion and proteomic profiles of the secretome after inhibiting the primary cilia gene intraflagellar transport particle 88 (Ift88) in microglia. Intriguingly, inhibiting primary cilia in the septal microglia 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 LS, 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. Targeting the primary ciliary signaling system could therefore be a viable strategy for modulating neuroimmune responses in AD treatments.

【 授权许可】

Unknown   
Copyright © 2023 Yeo, Jang, Jung, Lee and Choe.