Beta-amyloid/plasma lipoprotein interactions: Implications got vascular damage

Cardiovascular (CV) risk factors may be implicated in the pathogenesis of Alzheimer's disease (AD). The aim of this project was to examine potential pathological mechanisms whereby a common CV risk factor, hypercholesterolaemia, may modulate the onset and development of AD. A pathological hallmark of AD is the deposition of the cytotoxic peptide, beta amyloid (Aβ), in the walls of cerebral blood vessels. Platelets release Aβ upon activation and therefore subjects with conditions associated with platelet hyperactivity may be at increased risk of developing vascular amyloid deposits. Hypercholesterolaemia is associated with increased platelet activity, and affected individuals were investigated to establish if abnormal Aβ status was evident. Platelet Aβ release under resting and stimulated conditions was increased in hypercholesterolaemics in comparison with normocholesterolaemic individuals and correlated positively with plasma total cholesterol and low-density lipoprotein (LDL) cholesterol These data indicate that abnormal platelet Aβ release occurs in hypercholesterolaemia. Amyloid deposition in cerebral vessels is accompanied by smooth muscle cell degeneration, endothelial dysfunction and narrowing of the vessel lumen. Although soluble Aβ may produce pathological changes, it is generally accepted that Aβ toxicity relates to its aggregation state. Factors that promote Aβ aggregation are therefore potentially important with respect to the development of Aβ toxicity. Since plasma cholesterol has been shown to correlate with cerebral Aβ content, the influence of plasma lipoproteins upon Aβ fibrillogenesis was examined. In view of evidence that oxidative stress plays a role in the pathogenesis of both cardiovascular disease and AD, the influence of lipoprotein oxidation upon Aβ fibrillogenesis was also investigated. The chemical interactions between native and oxidised plasma lipoproteins and Aβ were studied extensively and therapeutically relevant strategies which may prevent lipoprotein mediated fibrillogenesis, including antioxidant and beta-sheet breaker peptide treatments, examined. Evidence for functional and pathophysiological roles for Aβ, including actions upon platelet and endothelial function as well as the modulation of vessel tone has been reported. In the present study, to establish if the biological effects of Aβ are potentiated by native and oxidised plasma lipoproteins, the actions of soluble, fibrillar and lipoprotein-treated Aβ preparations upon platelet function (aggregation and serotonin release), human aortic endothelial cell viability and rat aorta vasoactivity were studied. The results of these studies were compared with respect to the Aβ polymerisation state