BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1
Name
sciadv.abo1286.pdf
Description
Published version
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4.79 MB
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Checksum (MD5)
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Author(s)
Singh, Neeraj
Benoit, Marc R
Zhou, John
Das, Brati
Davila-Velderrain, Jose
Kellis, Manolis
Tsai, Li-Huei
Hu, Xiangyou
Yan, Riqiang
Date Issued
June 17, 2022
Journal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Singh, Neeraj, Benoit, Marc R, Zhou, John, Das, Brati, Davila-Velderrain, Jose et al. 2022. "BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1." Science Advances, 8 (24).
Version
Final published version
Abstract
BACE-1 is required for generating β-amyloid (Aβ) peptides in Alzheimer’s disease (AD). Here, we report that microglial BACE-1 regulates the transition of homeostatic to stage 1 disease-associated microglia (DAM-1) signature. BACE-1 deficiency elevated levels of transcription factors including Jun , Jund , Btg2 , Erg1 , Junb , Fos , and Fosb in the transition signature, which transition from more homeostatic to highly phagocytic DAM-1. Consistently, similar transition-state microglia in human AD brains correlated with lowered levels of BACE-1 expression. Targeted deletion of Bace-1 in adult 5xFAD mice microglia elevated these phagocytic microglia, correlated with significant reduction in amyloid plaques without synaptic toxicity. Silencing or pharmacologically inhibiting BACE-1 in cultured microglia-derived cells shows higher phagocytic function in microglia. Mechanistic exploration suggests that abolished cleavage of IL-1R2 and Toll-like receptors via BACE-1 inhibition contributes to the enhanced signaling via the PI3K and p38 MAPK kinase pathway. Together, targeted inhibition of BACE-1 in microglia may offer AD treatment.
BACE-1 is required for generating β-amyloid (Aβ) peptides in Alzheimer’s disease (AD). Here, we report that microglial BACE-1 regulates the transition of homeostatic to stage 1 disease-associated microglia (DAM-1) signature. BACE-1 deficiency elevated levels of transcription factors including Jun , Jund , Btg2 , Erg1 , Junb , Fos , and Fosb in the transition signature, which transition from more homeostatic to highly phagocytic DAM-1. Consistently, similar transition-state microglia in human AD brains correlated with lowered levels of BACE-1 expression. Targeted deletion of Bace-1 in adult 5xFAD mice microglia elevated these phagocytic microglia, correlated with significant reduction in amyloid plaques without synaptic toxicity. Silencing or pharmacologically inhibiting BACE-1 in cultured microglia-derived cells shows higher phagocytic function in microglia. Mechanistic exploration suggests that abolished cleavage of IL-1R2 and Toll-like receptors via BACE-1 inhibition contributes to the enhanced signaling via the PI3K and p38 MAPK kinase pathway. Together, targeted inhibition of BACE-1 in microglia may offer AD treatment.
MIT Department
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Picower Institute for Learning and Memory
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Creative Commons Attribution NonCommercial License 4.0
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DOI of Published Version
https://doi.org/10.1126/sciadv.abo1286
