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APP as a common denominator for Alzheimer's disease and osteoporosis

APP 是阿尔茨海默病和骨质疏松症的共同点

基本信息

批准号：
9323223
负责人：
WEN-CHENG XIONG
金额：
$ 9.39万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2017-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9323223
关键词：
Address Age Alpha Cell Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Precursor Animal Disease Models Animal Model Architecture Attenuated Bone Density Bone Marrow Bone Resorption Bone Tissue Bone structure Cell Lineage Cell surface Clinical Research Cognitive Comorbidity Degenerative Disorder Dementia Deterioration Disease Family Genes Genetic study Goals Hamsters Hip Fractures Homeostasis Impairment Integral Membrane Protein Iron Iron Chelation Knowledge Late Onset Alzheimer Disease Lead Ligands Link Mediating Molecular Mus Mutation Neurodegenerative Disorders Osteoblasts Osteoclasts Osteogenesis Osteopenia Osteoporosis Osteoporotic Pathologic Patients Play Population Presenile Alzheimer Dementia Prions Proteins Proteolysis Research Role Signal Transduction Swedish mutation Testing Tg2576 Transgenic Mice WNT Signaling Pathway age related aged biomarker development bone bone loss bone mass cell type hepcidin in vivo macrophage member mouse model mutant novel osteoblast differentiation osteoporotic bone promoter protein function public health relevance receptor risk variant selective expression skeletal substantia spongiosa young adult

项目摘要

DESCRIPTION (provided by applicant): Osteoporosis, a common skeletal degenerative disorder, is characterized by decrease of bone- mass and micro-architectural deterioration of bone tissue. Alzheimer's disease (AD) is a most common neurodegenerative disorder with cognitive dementia. Intriguingly, AD patients frequently have lower bone mineral density and higher rate of hip fracture, compared with the same age normal population. Several newly identified AD risk genes/loci encode proteins critical for osteoclastic activation and/or bone-mass homeostasis. Increasing evidence from clinical and genetic studies thus supports a degree of co-morbidity of both disorders. However, very few studies are available to address their relationship. The goal of this proposal is to determine if and how the Swedish mutant amyloid precursor protein (APPswe) acts as a common denominator for AD and osteoporosis/osteopenia. APP is a ubiquitously expressed transmembrane protein. Its cleavage product, A, is believed to be a major culprit for both early- and late-onset AD. We thus speculate that APP/A may contribute to the AD-associated skeletal deficits. By use of Tg2576 mice, a well-characterized AD animal model that ubiquitously expresses APPswe under the control of prion promoter, we observed age-dependent osteoporotic bone deficits in this animal model. By use of newly generated conditional/cell type specific APPswe transgenic mouse models, we found that APPswe plays important roles in regulating osteoblast (OB)-mediated bone formation and osteoclast (OC)-mediated bone resorption. However, the underlying mechanisms are unclear. In this proposal, we will address this issue. It is our hope that the results from this research may not only provide a potential link between AD and osteoporosis/osteopenia, but also identify unrecognized functions of APP and reveal new pathological mechanisms underlying both disorders.