Dataset Information

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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Jaemyung Jang

LAB HEAD: Youngshik Choe

PROVIDER: PXD043328 | Pride | 2024-01-26

REPOSITORIES: Pride

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

Yeo Seungeun S Jang Jaemyung J Jung Hyun Jin HJ Lee Hyeyoung H Choe Youngshik Y

Frontiers in molecular biosciences 20231023

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 difference ...[more]

PMID: 37942288

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Project description: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 (SEM) 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 less than 10% of microglia, and their presence was significantly reduced in microglia from AD mice. We observed significant changes in the expression and distribution of the secretome 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 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.

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