RRC ID 69823
Author Xie Z, Meng J, Kong W, Wu Z, Lan F, Narengaowa, Hayashi Y, Yang Q, Bai Z, Nakanishi H, Qing H, Ni J.
Title Microglial cathepsin E plays a role in neuroinflammation and amyloid β production in Alzheimer's disease.
Journal Aging Cell
Abstract Regulation of neuroinflammation and β-amyloid (Aβ) production are critical factors in the pathogenesis of Alzheimer's disease (AD). Cathepsin E (CatE), an aspartic protease, is widely studied as an inducer of growth arrest and apoptosis in several types of cancer cells. However, the function of CatE in AD is unknown. In this study, we demonstrated that the ablation of CatE in human amyloid precursor protein knock-in mice, called APPNL-G-F mice, significantly reduced Aβ accumulation, neuroinflammation, and cognitive impairments. Mechanistically, microglial CatE is involved in the secretion of soluble TNF-related apoptosis-inducing ligand, which plays an important role in microglia-mediated NF-κB-dependent neuroinflammation and neuronal Aβ production by beta-site APP cleaving enzyme 1. Furthermore, cannula-delivered CatE inhibitors improved memory function and reduced Aβ accumulation and neuroinflammation in AD mice. Our findings reveal that CatE as a modulator of microglial activation and neurodegeneration in AD and suggest CatE as a therapeutic target for AD by targeting neuroinflammation and Aβ pathology.
Volume 21(3)
Pages e13565
Published 2022-3-1
DOI 10.1111/acel.13565
PMID 35181976
PMC PMC8920437
MeSH Alzheimer Disease* / pathology Amyloid beta-Peptides* / metabolism Amyloid beta-Protein Precursor / genetics Amyloid beta-Protein Precursor / metabolism Animals Cathepsin E / genetics Cathepsin E / metabolism Disease Models, Animal Mice Mice, Inbred C57BL Mice, Transgenic Microglia / metabolism Neuroinflammatory Diseases
IF 7.238
Mice RBRC06344
Human and Animal Cells MG6(RCB2403)