Osteoporosis is a common skeletal degenerative disorder that is characterized by decrease of bone-mass and micro-architectural deterioration of bone tissue. It results from increased osteoclast (OC)-mediated bone resorption and/or reduced osteoblast (OB)-mediated bone formation. Alzheimer's disease (AD) is a 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 association of both disorders. However, very few studies are available to address the underlying mechanisms. The goal of this proposal is to determine if and how the Swedish mutant amyloid precursor protein (APPswe) acts as a risk factor for osteoporosis. 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 explored the possible contribution of APPswe to AD- associated skeletal deficits in mice. Tg2576 mice express APPswe under the control of prion promoter, and develop AD-relevant neuro-pathologic deficits at older age (>10 months old). Remarkably, our preliminary studies revealed age-dependent osteoporotic deficits in this AD animal model, including reduced trabecular bone-mass in young adult age and deteriorated bone tissue at older age. The reduced bone-mass was associated with a decrease in osteoblastic bone formation and an increase in osteoclastic bone resorption. The deteriorated bone structure was preceded by an impaired osteoclastic bone resorption. To investigate underlying mechanisms, we generated a transgenic mouse that enables cell-type specific expression of APPswe in OBs and OCs. Our results suggest that APPswe plays a cell autonomous role in suppressing OB-mediated bone formation and in regulating OC activation. These results uncovered potentially novel cellular mechanisms by which APPswe disrupts bone homeostasis. However, underlying molecular mechanisms remain unclear. In this proposal, we will address this issue. This research will not only provide a potential link between AD and skeletal deficits, but also identify unrecognized functions of APP and APPswe, and reveal new pathophysiological mechanisms underlying osteoporosis and AD, both chronic degenerative disorders affecting many veteran's quality of life and highly relevant to Strategic Objectives of VA.

Public Health Relevance

The goal of this proposal is to investigate functions and mechanisms of APP and Swedish mutant APP (APPswe) in regulating osteoblastic bone formation and osteoclastic bone resorption. It is relevant to our understanding of the pathogenesis of osteoporosis and Alzheimer's disorders (AD). Both osteoporosis and AD are older age associated disorders, which affects many veterans. Both disorders severely affect quality of life of aged veterans, but there is lack of cure treatment. It is our hope that the proposed research will provide useful information for not only our understanding of the pathogenesis of both disorders, but also the development of the strategy for early diagnosis and preventive therapy. Thus, they are highly relevant to the Research Objectives of VA.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX000838-05A1
Application #
9139032
Study Section
Endocrinology B (ENDB)
Project Start
2011-04-01
Project End
2020-09-30
Budget Start
2016-10-01
Budget End
2017-09-30
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Charlie Norwood VA Medical Center
Department
Type
DUNS #
010116408
City
Augusta
State
GA
Country
United States
Zip Code
30904