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.
