Unmasking BACE1 in aging and age-related diseases

Hong Bao; Yong Shen

doi:10.1016/j.molmed.2022.11.008

Unmasking BACE1 in aging and age-related diseases

Trends Mol Med. 2023 Feb;29(2):99-111. doi: 10.1016/j.molmed.2022.11.008. Epub 2022 Dec 9.

Authors

Hong Bao¹, Yong Shen²

Affiliations

¹ Institute on Aging and Brain Disorders, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
² Institute on Aging and Brain Disorders, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China; Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Anhui Provincial Key Laboratory of Biomedical Aging Research, University of Science and Technology of China, Hefei, 230026, China; CAS Key Laboratory of Brain Function and Disease, Division of Biological and Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China; Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China. Electronic address: yongshen@ustc.edu.cn.

PMID: 36509631
DOI: 10.1016/j.molmed.2022.11.008

Abstract

The beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) has long been considered a conventional target for Alzheimer's disease (AD). Unfortunately, AD clinical trials of most BACE1 inhibitors were discontinued due to ineffective cognitive improvement or safety challenges. Recent studies investigating the involvement of BACE1 in metabolic, vascular, and immune functions have indicated a role in aging, diabetes, hypertension, and cancer. These novel BACE1 functions have helped to identify new 'druggable' targets for BACE1 against aging comorbidities. In this review, we discuss BACE1 regulation during aging, and then provide recent insights into its enzymatic and nonenzymatic involvement in aging and age-related diseases. Our study not only proposes the perspective of BACE1's actions in various systems, but also provides new directions for using BACE1 inhibitors and modulators to delay aging and to treat age-related diseases.

Keywords: Alzheimer’s disease; BACE1; BACE1 inhibitors; age-related diseases; aging.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Aging / genetics
Alzheimer Disease* / drug therapy
Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Amyloid Precursor Protein Secretases* / genetics
Amyloid Precursor Protein Secretases* / metabolism
Amyloid beta-Protein Precursor / metabolism
Amyloid beta-Protein Precursor / therapeutic use
Aspartic Acid Endopeptidases / genetics
Aspartic Acid Endopeptidases / metabolism
Humans

Substances

Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
Amyloid beta-Protein Precursor
BACE1 protein, human