Targeted BACE-1 inhibition in microglia enhances amyloid clearance and improved cognitive performance

• Published in: Science advances 2022-07, Vol.8 (29), p.eabo3610
• Main Authors: Singh, Neeraj, Das, Brati, Zhou, John, Hu, Xiangyou, Yan, Riqiang
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Amyloid; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid Precursor Protein Secretases - metabolism; Animals; Aspartic Acid Endopeptidases - metabolism; Cellular Neuroscience; Cognition; Diseases and Disorders; Mammals - metabolism; Mice; Microglia - metabolism; Neuroscience; SciAdv r-articles; TOR Serine-Threonine Kinases
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abo3610

Abnormal accumulation of β-amyloid (Aβ) peptides is a culprit in Alzheimer's disease (AD); blocking Aβ generation is therefore being explored as a logical approach for AD treatment. Here, we demonstrate that targeted inhibition of β-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE-1) in microglia has unique advantages. When was deleted in Alzheimer's 5xFAD microglia, fewer amyloid plaques developed, and this reduction was not due to changes in APP processing but rather to enhanced Aβ clearance, in line with the increase in a microglial gene signature favoring phagocytosis. Moreover, deletion of in microglia enhances functions of autophagolysosomes and Aβ-induced metabolic reprogramming necessary for Aβ degradation by favoring phosphorylation of mammalian target of rapamycin complex (mTOR) at Ser and modulating the PI3K-mTOR-HIF-1α signaling pathways. Mice with deletion of in microglia showed no reduction in long-term potentiation, unlike global deletion of . Our results suggest that targeted inhibition of BACE-1 in microglia is a superior strategy for AD treatment.