Degradation of Bone Quality in a Transgenic Mouse Model of Alzheimer′s Disease

Abstract

Alzheimer′s disease (AD) patients present with symptoms such as impairment of insulin signaling, chronic inflammation, and oxidative stress. Furthermore, there are comorbidities associated with AD progression. For example, osteoporosis is common with AD wherein patients exhibit reduced mineralization and a risk for fragility fractures. However, there is a lack of understanding on the effects of AD on bone beyond loss of bone density. To this end, we investigated the effects of AD on bone quality using the 5XFAD transgenic mouse model in which 12‐month‐old 5XFAD mice showed accumulation of amyloid‐beta (Aβ42) compared with wild‐type (WT) littermates (n = 10/group; 50% female, 50% male). Here, we observed changes in cortical bone but not in cancellous bone quality. Both bone mass and bone quality, measured in femoral samples using imaging (micro‐CT, confocal Raman spectroscopy, X‐ray diffraction [XRD]), mechanical (fracture tests), and chemical analyses (biochemical assays), were altered in the 5XFAD mice compared with WT. Micro‐CT results showed 5XFAD mice had lower volumetric bone mineral density (BMD) and increased endocortical bone loss. XRD results showed decreased mineralization with smaller mineral crystals. Bone matrix compositional properties, from Raman, showed decreased crystallinity along with higher accumulation of glycoxidation products and glycation products, measured biochemically. 5XFAD mice also demonstrated loss of initiation and maximum toughness. We observed that carboxymethyl‐lysine (CML) and mineralization correlated with initiation toughness, whereas crystal size and pentosidine (PEN) correlated with maximum toughness, suggesting bone matrix changes predominated by advanced glycation end products (AGEs) and altered/poor mineral quality explained loss of fracture toughness. Our findings highlight two pathways to skeletal fragility in AD through alteration of bone quality: (i) accumulation of AGEs; and (ii) loss of crystallinity, decreased crystal size, and loss of mineralization. We observed that the accumulation of amyloidosis in brain correlated with an increase in several AGEs, consistent with a mechanistic link between elevated Aβ42 levels in the brain and AGE accumulation in bone. © 2022 American Society for Bone and Mineral Research (ASBMR).

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

“…Aβ42 can potently enhance osteoclast differentiation and activation but does not affect osteoclast cell viability or number ( 27 ). One study observed that 5XFAD mice had decreased volumetric BMD, elevated endocortical bone loss and reduced mineralization with smaller mineral crystals ( 28 ). 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 ).…”

“…One study observed that 5XFAD mice had decreased volumetric BMD, elevated endocortical bone loss and reduced mineralization with smaller mineral crystals ( 28 ). 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 ).…”

Amyloid-β neuropathology induces bone loss in male mice by suppressing bone formation and enhancing bone resorption

“…While we were writing our manuscript, another report described the skeletal phenotype of 5xFAD mice, revealing decreased mineralization, toughness, and quality of cortical bone with endocortical bone loss in both male and female 5xFAD mice at the age of 12 months ( LLabre et al, 2022 ). While sympathetic nervous system activity or circadian clock gene expression was not evaluated, the bone phenotype was found to reflect the accumulation of advanced glycation end products in the bone matrix.…”

Age- and sex-related differences of periodontal bone resorption, cognitive function, and immune state in APP/PS1 murine model of Alzheimer’s disease

“…Sex is one of the major risk factors for AD, with a higher incidence of the disease in females [ 41 ]. Osteoporosis is a common complication in women with AD, with patients exhibiting reduced mineralization and risk of fragility fractures [ 42 ]. Estrogen deficiency, in light of menopause, has distinctly been recognized as a major risk factor for osteoporosis in women [ 42 ].…”