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

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.