Amyloid-β as a Contributing Cause of Age-Related Cardiovascular Disease
Amyloid-β is one of the few proteins in the human body capable of misfolding in a way that encourages aggregation, causing the misfolded version to spread and form harmful deposits in tissues. This process is best known in the context of Alzheimer's disease, where an active debate continues over whether it is actually an important part of the condition or a side-effect of other important mechanisms. Amyloid-β aggregation also occurs in the cardiovascular system, however. There is some evidence for the presence of amyloid-β in brain and vasculature to be in a state of dynamic equilibrium, but equally the disease processes that arise in these two locations might still be largely independent of one another.
Aging-related cellular and molecular processes including low-grade inflammation are major players in the pathogenesis of cardiovascular disease (CVD) and Alzheimer's disease (AD). Epidemiological studies report an independent interaction between the development of dementia and the incidence of CVD in several populations, suggesting the presence of overlapping molecular mechanisms. Accumulating experimental and clinical evidence suggests that amyloid-beta (Aβ) peptides may function as a link among aging, CVD, and AD.
Experimental evidence indicates that Aβ peptides may be actively involved in downstream pathways leading to plaque rupture, thrombosis, and subsequent clinical manifestations of the acute coronary syndrome (ACS). Αβ1-40 stimulates platelet activation and adhesion in humans and mice and induces release of matrix metalloproteinases by human monocytes to increase plaque vulnerability. Although patients with coronary artery disease (CAD) are more likely to develop AD-like neuropathological lesions than those without CAD, whether atherogenesis occurs in parallel or independently from brain parenchyma amyloid load in humans is unknown.
A pathophysiological role of Aβ1-40 across the continuum of cardiovascular disease is suggested through its independent association with a broad spectrum of vascular and cardiac involvement from early functional vascular alterations and subclinical atherosclerosis to overt symptomatic CAD, ACS, and heart failure. This is robustly supported by experimental evidence that amyloid precursor protein (APP) and Aβ1-40 are critically involved in vascular inflammation, vascular and cardiac aging, and atherothrombosis. Thus, Aβ1-40 fulfills several criteria for consideration as a new biomarker for risk stratification in cardiovascular disease.
Most importantly, multiple lines of evidence clearly indicate that manipulating APP/Aβ turnover and aggregation or blocking its inflammatory reactions is feasible, potentially improving our understanding and means to simultaneously protect the brain, heart, and vessels during physiological or premature aging.