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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG051773-06
Application #
9903240
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Williams, John
Project Start
2016-08-15
Project End
2021-04-30
Budget Start
2020-05-15
Budget End
2021-04-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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