Degradation of Bone Quality in a Transgenic Mouse Model of Alzheimer's Disease.
5XFAD TRANSGENIC MOUSE MODEL
ALZHEIMER′S DISEASE
BIOMECHANICS
BONE QCT/MICRO-CT
GLYCOXIDATION
Journal
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
ISSN: 1523-4681
Titre abrégé: J Bone Miner Res
Pays: United States
ID NLM: 8610640
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
revised:
03
10
2022
received:
02
04
2022
accepted:
14
10
2022
pubmed:
18
10
2022
medline:
22
12
2022
entrez:
17
10
2022
Statut:
ppublish
Résumé
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).
Identifiants
pubmed: 36250342
doi: 10.1002/jbmr.4723
pmc: PMC9772191
mid: NIHMS1856379
doi:
Substances chimiques
Amyloid beta-Peptides
0
Glycation End Products, Advanced
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2548-2565Subventions
Organisme : NIA NIH HHS
ID : R21 AG063063
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG057464
Pays : United States
Organisme : NIA NIH HHS
ID : A131351094
Pays : United States
Organisme : NIA NIH HHS
ID : T32AG057464
Pays : United States
Informations de copyright
© 2022 American Society for Bone and Mineral Research (ASBMR).
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