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

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

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

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.

if you want to read this article from the original credit source of the article then you can read from here

.

Best Offer Mansoon Sell Today Up to 75% Off



Leave a Reply