The over-arching area of enquiry of the original RO1 (AG19250) was to understand the origin of the cerebrovascular abnormalities characteristic of Alzheimer's Disease (AD). Numerous structural and functional cerebromicrovascular abnormalities have been identified in AD subjects, including decreased capillary diameter and microvessel density, thinning of capillary basement membrane, attenuation of capillary endothelium and cerebrovascular muscle atrophy supporting the possibility of an alternation of the angiogenic process in AD brain. Microvessels undergoing angiogenesis and sprouting, normally proliferate by growth of the endothelium, which subsequently secretes the basement membrane. The opposite result has been observed in Alzheimer's disease, where microvessels associated with Abeta deposits displayed non-functional endothelium along with thinning of the basement membrane. To understand how the cerebrovascular pathological abnormalities of AD occur we first focused on the prostaglandin producing pro-inflammatory sPLA2-MAPK-cPLA2-AA-LOX/COX pathway is activated in the vasculature which we have shown is activated by low doses of freshly solubilized Abeta.
The specific aims of the current proposal have arisen directly from our observations made in R01 NIA-AG19250 the results of which are detailed below. Observation that the sPLA2-MAPK-cPLA2-AA-LOX-COX pathway is activated in the vasculature by Abeta load us to the question of whether Abeta could stimulate an imflammatory angiogenesis. Surprisingly we found that although at low doses of Abeta there is evidence that Aa can stimulate angiogenesis at higher doses (with greater aggregation of Abeta) a profound anti-angiogenic response occurs. We have explored the anti-angiogenic response of Abeta for two distinct reasons: firstly it could account for some of the pathological cerebrovascular pathologies observed in the course of the AD process and secondly Abeta or related peptides may be a potential candidate for anti-tumor therapies based on it's antiangiogenic properties. The purpose of this proposal is to increase our understanding of how and why Abeta has such potent anti-angiogenic properties.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG019250-05
Application #
6872813
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Petanceska, Suzana
Project Start
2001-04-01
Project End
2010-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
5
Fiscal Year
2005
Total Cost
$290,583
Indirect Cost
Name
Roskamp Institute, Inc.
Department
Type
DUNS #
119173933
City
Sarasota
State
FL
Country
United States
Zip Code
34243
Paris, Daniel; Patel, Nikunj; Ganey, Nowell J et al. (2010) Anti-Tumoral Activity of a Short Decapeptide Fragment of the Alzheimer's Abeta Peptide. Int J Pept Res Ther 16:23-30
Paris, Daniel; Ganey, Nowel; Banasiak, Magdalena et al. (2010) Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer's disease. J Neurosci 30:11251-8
Paris, Daniel; Ait-Ghezala, Ghania; Mathura, Venkatarajan S et al. (2005) Anti-angiogenic activity of the mutant Dutch A(beta) peptide on human brain microvascular endothelial cells. Brain Res Mol Brain Res 136:212-30
Paris, Daniel; Humphrey, James; Quadros, Amita et al. (2003) Vasoactive effects of A beta in isolated human cerebrovessels and in a transgenic mouse model of Alzheimer's disease: role of inflammation. Neurol Res 25:642-51
Paris, Daniel; Townsend, Kirk P; Obregon, Demian F et al. (2002) Pro-inflammatory effect of freshly solubilized beta-amyloid peptides in the brain. Prostaglandins Other Lipid Mediat 70:1-12
Townsend, K P; Obregon, D; Quadros, A et al. (2002) Proinflammatory and vasoactive effects of Abeta in the cerebrovasculature. Ann N Y Acad Sci 977:65-76