title: APPswe/Aβ regulation of osteoclast activation and RAGE expression in an age-dependent manner.
abstract: Alzheimer's disease (AD), one of the most dreaded neurodegenerative disorders, is characterized by cortical and cerebrovascular amyloid β peptide (Aβ) deposits, neurofibrillary tangles, chronic inflammation, and neuronal loss. Increased bone fracture rates and reduced bone density are commonly observed in patients with AD, suggesting one or more common denominators between both disorders. However, very few studies are available that have addressed this issue. Here, we present evidence for a function of amyloid precursor protein (APP) and Aβ in regulating osteoclast (OC) differentiation in vitro and in vivo. Tg2576 mice, which express the Swedish mutation of APP (APPswe) under the control of a prion promoter, exhibit biphasic effects on OC activation, with an increase of OCs in younger mice (< 4 months old), but a decrease in older Tg2576 mice (> 4 months old). The increase of OCs in young Tg2576 mice appears to be mediated by Aβ oligomers and receptor for advanced glycation end products (RAGE) expression in bone marrow macrophages (BMMs). However, the decrease of OC formation and activity in older Tg2576 mice may be due to the increase of soluble rage (sRAGE) in aged Tg2576 mice, an inhibitor of RANKL-induced osteoclastogenesis. These results suggest an unexpected function of APPswe/Aβ, reveal a mechanism underlying altered bone remodeling in AD patients, and implicate APP/Aβ and RAGE as common denominators for both AD and osteoporosis.
authors.affiliation: Institute of Molecular Medicine & Genetics and Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Shun
authors.initials: S
authors.lastname: Cui
authors.forename: Fei
authors.initials: F
authors.lastname: Xiong
authors.forename: Yan
authors.initials: Y
authors.lastname: Hong
authors.forename: Ji-Ung
authors.initials: JU
authors.lastname: Jung
authors.forename: Xing-Sheng
authors.initials: XS
authors.lastname: Li
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Liu
authors.forename: Riqiang
authors.initials: R
authors.lastname: Yan
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.forename: Xu
authors.initials: X
authors.lastname: Feng
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009929:Organ Size; D009928:Organ Specificity / Q000187:drug effects; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D020836:Protein Structure, Quaternary; D053245:RANK Ligand / Q000494:pharmacology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000008:administration & dosage / Q000378:metabolism*; D012995:Solubility / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D053245:RANK Ligand; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic