| Summary: | <jats:p>
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
<jats:italic>Jun</jats:italic>
,
<jats:italic>Jund</jats:italic>
,
<jats:italic>Btg2</jats:italic>
,
<jats:italic>Erg1</jats:italic>
,
<jats:italic>Junb</jats:italic>
,
<jats:italic>Fos</jats:italic>
, and
<jats:italic>Fosb</jats:italic>
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
<jats:italic>Bace-1</jats:italic>
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.
</jats:p>
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