Endogenous Aβ induces osteoporosis through an mTOR-dependent inhibition of autophagy in bone marrow mesenchymal stem cells (BMSCs)

Abstract

Background: It has previously been suggested that Alzheimer's disease (AD) and osteoporosis (OP) were related. However, the connection between these 2 disorders is poorly understood. This study aimed to investigate the relationship between amyloid β peptide (Aβ) and the osteoporotic deficit observed in AD patients.Methods: We used the APP/PS1ΔE9 transgenic mouse model of AD for in vivo study and extracted bone marrow mesenchymal stem cells (BMSCs) for in vitro studies. For in vivo experiments, mice femurs were put through a μ-computer tomography (μ-CT) scanning and after which, sliced for hematoxylin/eosin (HE), Masson and Goldner staining for detection of bone changes. For in vitro experiments, BMSCs were placed in an osteogenic inducing medium with or without rapamycin. After induction, alkaline phosphatase (ALP) staining, alizarin red staining, quantitative real-time PCR (qPCR) and western-blot were used to identify osteogenic differentiation, calcium deposition and protein expression differences respectively. Results:We observed that pathological changes characteristic of AD and OP occurred in vivo in APP/ PS1ΔE9 mice. In BMSCs producing endogenous Aβ, mammalian target of rapamycin (mTOR) activation and subsequent inhibition of autophagy suppressed bone formation. Further, the addition of the mTOR inhibitor rapamycin into the inducing medium reversed the inhibition of osteogenesis.Conclusions: Our results suggested that endogenous Aβ might have induced osteoporosis through an mTOR-dependent inhibition of autophagy in BMSCs, which may explain the OP changes observed in AD patients.

Alzheimer’s disease and its associated risk of bone fractures: a narrative review

“…Two pathways were found to be contributing to skeletal fragility in AD via alteration of bone quality: accumulation of AGEs and lack of crystallinity, reduced crystal size, and lack of mineralization ( 28 ). Another animal study showed that endogenous Aβ might induce osteoporosis via mTOR-dependent inhibition of autophagy in bone marrow mesenchymal stem cells (BMSCs) ( 29 ). Therefore, APP/Aβ has direct effects on bone cells and may play a vital function in the pathogenesis of bone fractures in AD patients.…”

Recent advances of the mammalian target of rapamycin signaling in mesenchymal stem cells

“…It has been reported that activation/inhibition of mTOR signaling positively/negatively regulates BMSC/osteoblast-mediated bone formation, adipogenic differentiation, osteoblast homeostasis, and osteoclast mediated bone resorption, leading to altered bone homeostasis, which can lead to or prevent osteoporosis (Shen et al, 2018). Other studies have shown that amyloid β induces osteoporotic defects in vivo and in vitro through mTOR and autophagy, and the regulation of amyloid β on BMSCs is dependent on mTOR, thus providing a possible mechanism for osteoporotic remodeling in AD patients (Yang et al, 2019;Lin et al, 2021).…”

Citropten Ameliorates Osteoclastogenesis Related to MAPK and PLCγ/Ca2+ Signaling Pathways through the Regulation of Amyloid Beta

“…26 It is also reported that bone marrow mesenchymal stem cells (BMSCs) producing endogenous Aβ, which led to the activation of mammalian target of rapamycin (mTOR) and consequent inhibition of autophagy, impede the bone formation. 27 Additionally, supplementation of the inducing medium with mTOR inhibitor rapamycin reversed the inhibition of osteogenesis in vivo. 27 In vertebral trabecular bone specimens from a 45 female patient group with fresh vertebral compression fractures, osteoporotic bone tissues showed higher levels of Aβ peptide, which enhances osteoclast function.…”

“…27 Additionally, supplementation of the inducing medium with mTOR inhibitor rapamycin reversed the inhibition of osteogenesis in vivo. 27 In vertebral trabecular bone specimens from a 45 female patient group with fresh vertebral compression fractures, osteoporotic bone tissues showed higher levels of Aβ peptide, which enhances osteoclast function. 25 In this study, we used the RANKL-induced osteoclast pretreated with Aβ model in vitro to examine the inhibitory effect of CTP on osteoclast differentiation, function, and related genes and proteins.…”

“…Besides, a previous study indicated that Aβ increased nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) activity, α (IκB-α) degradation, activated extracellular signal-regulated kinase (ERK) phosphorylation, nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, and stimulated calcium oscillation . It is also reported that bone marrow mesenchymal stem cells (BMSCs) producing endogenous Aβ, which led to the activation of mammalian target of rapamycin (mTOR) and consequent inhibition of autophagy, impede the bone formation . Additionally, supplementation of the inducing medium with mTOR inhibitor rapamycin reversed the inhibition of osteogenesis in vivo .…”