1. ArhGAP11A mediates amyloid-β generation and neuropathology in an Alzheimer's disease-like mouse model.
- Author
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Huang YR, Xie XX, Yang J, Sun XY, Niu XY, Yang CG, Li LJ, Zhang L, Wang D, Liu CY, Hou SJ, Jiang CY, Xu YM, and Liu RT
- Subjects
- Animals, Mice, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor metabolism, Amyloid Precursor Protein Secretases metabolism, Aspartic Acid Endopeptidases metabolism, Disease Models, Animal, Mice, Transgenic, Presenilin-1 metabolism, Alzheimer Disease metabolism, GTPase-Activating Proteins metabolism
- Abstract
Amyloid-β (Aβ) plays an important role in the neuropathology of Alzheimer's disease (AD), but some factors promoting Aβ generation and Aβ oligomer (Aβo) neurotoxicity remain unclear. We here find that the levels of ArhGAP11A, a Ras homology GTPase-activating protein, significantly increase in patients with AD and amyloid precursor protein (APP)/presenilin-1 (PS1) mice. Reducing the ArhGAP11A level in neurons not only inhibits Aβ generation by decreasing the expression of APP, PS1, and β-secretase (BACE1) through the RhoA/ROCK/Erk signaling pathway but also reduces Aβo neurotoxicity by decreasing the expressions of apoptosis-related p53 target genes. In APP/PS1 mice, specific reduction of the ArhGAP11A level in neurons significantly reduces Aβ production and plaque deposition and ameliorates neuronal damage, neuroinflammation, and cognitive deficits. Moreover, Aβos enhance ArhGAP11A expression in neurons by activating E2F1, which thus forms a deleterious cycle. Our results demonstrate that ArhGAP11A may be involved in AD pathogenesis and that decreasing ArhGAP11A expression may be a promising therapeutic strategy for AD treatment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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