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BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1

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, J...

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Autores principales: Singh, Neeraj, Benoit, Marc R., Zhou, John, Das, Brati, Davila-Velderrain, Jose, Kellis, Manolis, Tsai, Li-Huei, Hu, Xiangyou, Yan, Riqiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9205595/
https://www.ncbi.nlm.nih.gov/pubmed/35714196
http://dx.doi.org/10.1126/sciadv.abo1286
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author Singh, Neeraj
Benoit, Marc R.
Zhou, John
Das, Brati
Davila-Velderrain, Jose
Kellis, Manolis
Tsai, Li-Huei
Hu, Xiangyou
Yan, Riqiang
author_facet Singh, Neeraj
Benoit, Marc R.
Zhou, John
Das, Brati
Davila-Velderrain, Jose
Kellis, Manolis
Tsai, Li-Huei
Hu, Xiangyou
Yan, Riqiang
author_sort Singh, Neeraj
collection PubMed
description 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.
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spelling pubmed-92055952022-06-29 BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1 Singh, Neeraj Benoit, Marc R. Zhou, John Das, Brati Davila-Velderrain, Jose Kellis, Manolis Tsai, Li-Huei Hu, Xiangyou Yan, Riqiang Sci Adv Neuroscience 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. American Association for the Advancement of Science 2022-06-17 /pmc/articles/PMC9205595/ /pubmed/35714196 http://dx.doi.org/10.1126/sciadv.abo1286 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Neuroscience
Singh, Neeraj
Benoit, Marc R.
Zhou, John
Das, Brati
Davila-Velderrain, Jose
Kellis, Manolis
Tsai, Li-Huei
Hu, Xiangyou
Yan, Riqiang
BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1
title BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1
title_full BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1
title_fullStr BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1
title_full_unstemmed BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1
title_short BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1
title_sort bace-1 inhibition facilitates the transition from homeostatic microglia to dam-1
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9205595/
https://www.ncbi.nlm.nih.gov/pubmed/35714196
http://dx.doi.org/10.1126/sciadv.abo1286
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