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

ANNALS OF TRANSLATIONAL MEDICINE(2021)

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摘要
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 13 peptide (A13) and the osteoporotic deficit observed in AD patients. Methods: We used the APP/PS1AE9 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 mu-computer tomography (mu-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/ PS1AE9 mice. In BMSCs producing endogenous A13, 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 A13 might have induced osteoporosis through an mTOR-dependent inhibition of autophagy in BMSCs, which may explain the OP changes observed in AD patients.
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关键词
Amyloid 13 (A13), osteoporosis, Alzheimer's disease (AD), bone marrow mesenchymal stem cells (BMSCs), mTOR
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