Extracellular deposition of the amyloid ?-protein (A?) in brain is a prominent pathological feature of Alzheimer's disease (AD) and related disorders. Cerebral parenchymal A? deposition can occur as diffuse plaques, with little surrounding pathology, or as fibrillar plaques associated with dystrophic neurons and inflammation. Fibrillar A? deposition in the cerebral vasculature, a condition known as cerebral amyloid angiopathy (CAA), is also commonly found in Alzheimer's disease. Additionally, several familial monogenic forms of CAA exist that result from mutations that reside within the A? peptide sequence of ASPP gene including Dutch- type (E22Q) and Iowa-type (D23N) which cause early and severe cerebral vascular amyloid deposition. Recent studies have implicated cerebral microvascular AS deposition in promoting neuroinflammation and dementia in patients with CAA. Cerebral microvascular, but not parenchymal, amyloid deposition is more often correlated with dementia in individuals afflicted with Alzheimer's disease and CAA. Neuroinflammation remains a viable target for the treatment of amyloid-depositing diseases in the central nervous system, particularly the neuroinflammation associated with cerebral microvascular amyloid. Recently, we generated novel transgenic mice that express human vasculotropic Dutch/Iowa mutant human amyloid B-protein precursor (ASPP) in brain, designated Tg-SwDI, that develop early-onset and robust fibrillar cerebral microvascular A? deposition in the absence of parenchymal fibrillar plaque amyloid. More recent work from our laboratory has demonstrated that Tg-SwDI mice exhibit neuroinflammation that is strongly associated with the cerebral microvascular amyloid deposition. Furthermore, Tg-SwDI mice show marked deficits in behavioral performance. In light of these findings, the overall hypothesis that forms the basis for this proposal is that cerebral microvascular fibrillar AB deposition promotes neuroinflammation and behavioral deficits in the absence of fibrillar plaque amyloid. In the present proposal, we plan to thoroughly characterize the microvascular amyloid and the neuroinflammatory response, as well as investigate the effects of anti-inflammatory drug treatment on modulating microvascular amyloid, neuroinflammation, and behavioral decline in Tg-SwDI mice, a novel and unique transgenic model that only develops microvascular fibrillar A? deposition. Completion of these studies should provide important insight into microvascular amyloid-mediated neuroinflammation and dementia that is an understudied and likely important, aspect of disorders that involve CAA. Additionally, since CAA pathology is commonly found in Alzheimer's disease this pathologic target may have far reaching implications in combined treatment strategies for this neurodegenerative condition and its related CAA disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055118-03
Application #
7561078
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sieber, Beth-Anne
Project Start
2007-02-01
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
3
Fiscal Year
2009
Total Cost
$337,399
Indirect Cost
Name
State University New York Stony Brook
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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Hu, Zishuo Ian; Kotarba, Ann Marie E; Van Nostrand, William E (2013) Absence of Nitric Oxide Synthase 3 Increases Amyloid ?-Protein Pathology in Tg-5xFAD Mice. Neurosci Med 4:84-91
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Park, Laibaik; Wang, Gang; Zhou, Ping et al. (2011) Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-beta. Proc Natl Acad Sci U S A 108:5063-8
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Liao, Mei-Chen; Van Nostrand, William E (2010) Degradation of soluble and fibrillar amyloid beta-protein by matrix metalloproteinase (MT1-MMP) in vitro. Biochemistry 49:1127-36
Van Nostrand, William E; Xu, Feng; Rozemuller, Annemieke J M et al. (2010) Enhanced capillary amyloid angiopathy-associated pathology in Tg-SwDI mice with deleted nitric oxide synthase 2. Stroke 41:S135-8
Wilcock, Donna M; Gharkholonarehe, Nastaran; Van Nostrand, William E et al. (2009) Amyloid reduction by amyloid-beta vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer's disease. J Neurosci 29:7957-65
Wilcock, Donna M; Lewis, Matthew R; Van Nostrand, William E et al. (2008) Progression of amyloid pathology to Alzheimer's disease pathology in an amyloid precursor protein transgenic mouse model by removal of nitric oxide synthase 2. J Neurosci 28:1537-45

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