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.

中文翻译：

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BACE-1 抑制促进从稳态小胶质细胞向 DAM-1 的转变

BACE-1 是阿尔茨海默病 (AD) 中生成 β-淀粉样蛋白 (Aβ) 肽所必需的。在这里，我们报告小胶质细胞 BACE-1 调节稳态向 1 期疾病相关小胶质细胞 (DAM-1) 特征的转变。BACE-1 缺乏会升高转录因子的水平，包括君,勇德,Btg2,Erg1,军布,福斯， 和磷脂在过渡特征中，从更稳态的 DAM-1 过渡到高度吞噬的 DAM-1。一致地，人类 AD 大脑中类似的过渡态小胶质细胞与 BACE-1 表达水平降低相关。针对性删除Bace-1在成年 5xFAD 小鼠中，小胶质细胞升高了这些吞噬性小胶质细胞，与淀粉样斑块的显着减少相关，而没有突触毒性。在培养的小胶质细胞衍生细胞中沉默或药理学抑制 BACE-1 显示小胶质细胞具有更高的吞噬功能。机制探索表明，通过抑制 BACE-1 消除 IL-1R2 和 Toll 样受体的切割有助于通过 PI3K 和 p38 MAPK 激酶通路增强信号传导。总之，靶向抑制小胶质细胞中的 BACE-1 可能会提供 AD 治疗。