Cardiac functional and structural impairments, endothelial apoptosis and blood-brain barrier dysfunction in models of cerebrovascular amyloidosis in the presence or absence of hyperhomocysteinemia

Cerebrovascular dysfunction has been implicated as a major early contributor to Alzheimer's Disease (AD) pathology, with endothelial cell (EC) stress resulting in focal ischemia, cerebral blood flow impairments, and blood brain barrier (BBB) permeability. Recent evidence suggests that cardiovascular (CV)/cerebrovascular risk factors, such as hyperhomocysteinemia (Hhcy) contribute to increasing AD pathology and risk, but it remains unknown whether Amyloid beta (Aβ) and homocysteine function through common molecular mechanisms to induce EC dysfunction. Additionally, Aβ is known to mediate degeneration of the brain neuro-signaling pathways. Neurotrophic factors depletion, together with vascular and peripheral amyloid accumulation, may also result in the derangement of the peripheral nervous system, culminating in detrimental effects on other organs, including the heart. However, whether and how AD pathology modulates cardiac function, cardiac amyloidosis and heart innervation is still unknown. Here, we will discuss two important and new mechanistic perspectives on the vascular contributions to cognitive impairment and dementia: