The Alzheimer’s Disease Amyloid-Beta Hypothesis in Cardiovascular Aging and Disease

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. Aging-related vascular and cardiac deposition of Αβ induces tissue inflammation and organ dysfunction, both important components of the Alzheimer’s disease amyloid hypothesis. In this review, the authors describe the determinants of Aβ metabolism, summarize the effects of Aβ on atherothrombosis and cardiac dysfunction, discuss the clinical value of Αβ1-40 in CVD prognosis and patient risk stratification, and present the therapeutic interventions that may alter Aβ metabolism in humans.


Supplemental Table 3. Diseases and other molecular and genetic determinants of A abundance Diseases associated with A abundance and other molecular determinants
Effector Effect Tissue / cell specificity Source Down Syndrome ↑ Human hippocampal, prefrontal and frontal brain sections (64,65)

Chronic obstructive pulmonary disease
Association with increased A1-40 and Aβ1-42 Human blood plasma probes (73)

Lys670Asn and Met671Leu
Increased A generation studied in a human fibroblast cell line (82)

Intervention/condition Cell type/Population Effects on Aβ metabolism Source Smoking
APPswe/PS1dE9 transgenic mice Smoking promotes the formation of new total Aβ deposits in neurons and microglial cells (87) High fat diet APP transgenic mice High fat diet promotes APP cleavage by BACE1 in neurons (88)

Anticoagulants Intervention/condition Cell type/Population Effects on Aβ metabolism Source
Heparin PC12 mice cells Heparin attenuates toxic effects induced by Αβ (94) Enoxaparin APP23 transgenic mice Enoxaparin reduces Αβ and amyloid plaques in brain (95) Heparin SHSY5Y neuroblastoma cells Heparin inhibits BACE1 and APP cleavage in neurons (96) Heparin

Recombinant human BACE1 incubated with heparin
In low concentration, heparin stimulates BACE1 activity and its autocatalysis, while in high concentration, heparin inhibits BACE1 (97) Heparin Human neuroblastoma cells Increased neuronal secretion of total APP and sAPPβ (98) Heparin