Targeting autophagy receptors OPTN and SQSTM1 as a novel therapeutic strategy for osteoporosis complicated with Alzheimer's disease

Ran Duan; Chun-Gu Hong; Meng-Lu Chen; Xin Wang; Zhi-Lin Pang; Hui Xie; Zheng-Zhao Liu

doi:10.1016/j.cbi.2023.110462

Targeting autophagy receptors OPTN and SQSTM1 as a novel therapeutic strategy for osteoporosis complicated with Alzheimer's disease

Chem Biol Interact. 2023 May 25:377:110462. doi: 10.1016/j.cbi.2023.110462. Epub 2023 Mar 22.

Authors

Ran Duan¹, Chun-Gu Hong², Meng-Lu Chen¹, Xin Wang³, Zhi-Lin Pang³, Hui Xie⁴, Zheng-Zhao Liu⁵

Affiliations

¹ Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
² Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
³ Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
⁴ Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. Electronic address: huixie@csu.edu.cn.
⁵ Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. Electronic address: liuzhengzhao@csu.edu.cn.

PMID: 36958424
DOI: 10.1016/j.cbi.2023.110462

Abstract

Alzheimer's disease (AD) is a common degenerative disease among the elderly population. In addition to cognitive impairment, AD is often accompanied by behavioral manifestations. However, little attention has been paid to changes in bone metabolism and related mechanisms in patients with AD. We found that AD mice (APPswe/PS1dE9) had reduced bone density, weakened bone strength, and amyloid beta (Aβ) deposition in the bone tissue. It was further found that targeting autophagy receptors Optineurin (OPTN) and Sequestosome 1 (SQSTM1) increased bone density and bone strength in AD mice, promoted the clearance of Aβ in the bone tissue, and maintained bone homeostasis. Our study suggests that abnormal Aβ deposition may be the co-pathogenesis of AD and osteoporosis (OP). Targeting OPTN and SQSTM1 has a dual-functional effect of alleviating both AD and OP through selective autophagy that specifically targets Aβ for clearance. Therapeutic strategies targeting autophagy may help guide the treatment of patients with AD complicated with OP.

Keywords: Alzheimer's disease; Autophagy; OPTN; Osteoporosis; SQSTM1.

MeSH terms

Aged
Alzheimer Disease* / complications
Alzheimer Disease* / drug therapy
Alzheimer Disease* / metabolism
Amyloid beta-Peptides / metabolism
Animals
Autophagy
Carrier Proteins
Cell Cycle Proteins / metabolism
Disease Models, Animal
Humans
Membrane Transport Proteins
Mice
Mice, Transgenic
Osteoporosis* / drug therapy
Sequestosome-1 Protein / metabolism

Substances

Amyloid beta-Peptides
Sequestosome-1 Protein
Carrier Proteins
SQSTM1 protein, human
Sqstm1 protein, mouse
Optn protein, mouse
Cell Cycle Proteins
Membrane Transport Proteins