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:Our new mechanistic data demonstrates that Hhcy specifically potentiates Aβ-mediated activation of the death receptors 4/5 (DR4/5)-mediated extrinsic apoptotic pathway in cerebral ECs. Additionally, we revealed that Hhcy potentiates Aβ-mediated EC barrier permeability, deregulating specific junction proteins expression, localization, and phosphorylation. Moreover, Hhcy and Aβ impair VEGF-A and VEGFR2 signaling and VEGFR2 endosomal trafficking, additively decreasing EC angiogenic capabilities. This work highlights new potential molecular targets against cerebrovascular pathology in comorbid AD/CAA and Hhcy conditions.We will describe the first report of cardiac remodeling, amyloid deposition, and neuro-signaling dysregulation in the heart of Tg2576 mice, a widely used model of AD and cerebral amyloidosis. Tg2576 mice hearts exhibited an accumulation of amyloid aggregates, including Aβ40, together with a robust reduction in NGF and BDNF protein expression, leading to interstitial fibrosis and severe cardiac nervous system dysfunction. The transgenic mice also showed a significant decrease in cardiac adrenergic and regenerating nerve endings. Our data suggest that AD amyloid pathology can cause deleterious functional effects on the heart, and the peripheral neurotrophic pathway may represent a potential therapeutic target to limit these effects.