This review summarizes recent evidence on how mid-life hypertension, hyperhomocysteinemia (HHcy) and blood pressure variability, as well as late-life hypotension, exacerbate Alzheimer's disease (AD) and dementia risk. Intriguingly, HHcy also increases the risk for hypertension, revealing the importance of understanding the relationship between comorbid cardiovascular risk factors. Hypertension-induced dementia presents more evidently in women, highlighting the relevance of sex differences in the impact of cardiovascular risk. We summarize each major antihypertensive drug class's effects on cognitive impairment and AD pathology, revealing how carbonic anhydrase inhibitors, diuretics modulating cerebral blood flow, have recently gained preclinical evidence as promising treatment against AD. We also report novel vascular biomarkers for AD and dementia risk, highlighting those associated with hypertension and HHcy. Importantly, we propose that future studies should consider hypertension and HHcy as potential contributors to cognitive impairment, and that uncovering the underlying molecular mechanisms and biomarkers would aid in the identification of preventive strategies.

Cerebrovascular dysfunction has been implicated as a major contributor to Alzheimers Disease (AD) pathology, with cerebral endothelial cell (cEC) stress promoting ischemia, cerebral-blood flow impairments and blood-brain barrier (BBB) permeability. Recent evidence suggests that cardiovascular (CV)/cerebrovascular risk factors, including hyperhomocysteinemia (Hhcy), exacerbate AD pathology and risk. Yet, the underlying molecular mechanisms for this interaction remain unclear. Our lab has demonstrated that amyloid beta 40 (Aβ40) species, and particularly Aβ40-E22Q (vasculotropic Dutch mutant), promote death receptor 4 and 5 (DR4/DR5)-mediated apoptosis in human cECs, barrier permeability and angiogenic impairment. Previous studies show that Hhcy also induces EC dysfunction, but it remains unknown whether Aβ and homocysteine function through common molecular mechanisms. We tested the hypotheses that Hhcy exacerbates Aβ-induced cEC DR4/5-mediated apoptosis, barrier dysfunction, and angiogenesis defects. This study was the first to demonstrate that Hhcy specifically potentiates Aβ40-E22Q-mediated activation of the DR4/5-mediated extrinsic apoptotic pathway in cECs, including DR4/5 expression, caspase 8/9/3 activation, cytochrome-c release and DNA fragmentation. Additionally, we revealed that Hhcy intensifies the deregulation of the same cEC junction proteins mediated by Aβ, precipitating BBB permeability. Furthermore, Hhcy and Aβ40-E22Q, impairing VEGF-A/VEGFR2 signaling and VEGFR2 endosomal trafficking, additively decrease cEC angiogenic capabilities. Overall, these results show that the presence of the CV risk factor Hhcy exacerbates Aβ-induced cEC apoptosis, barrier dysfunction, and angiogenic impairment. This study reveals specific mechanisms through which amyloidosis and Hhcy jointly operate to produce brain EC dysfunction and death, highlighting new potential molecular targets against vascular pathology in comorbid AD/CAA and Hhcy conditions.

BackgroundCerebrovascular dysfunction has been implicated as a major contributor to Alzheimer’s Disease (AD) pathology, with particularly endothelial cell (EC) stress promoting the focal ischemia, cerebral blood flow impairments, and blood brain barrier (BBB) permeability that are pathologically characteristic in AD. Recent evidence has emerged suggesting a link between cardiovascular (CV) diseases and AD pathology, particularly showing that CV/cerebrovascular risk factors, including hyperhomocysteinemia (Hhcy) and hypoperfusion (oxygen and glucose deprivation (OGD)), contribute to AD pathology and risk. Despite this, the underlying molecular mechanisms for this interaction remain unclear. Previously our lab has demonstrated that amyloid beta (Aβ), particularly Aβ40‐Q22 (the vasculotropic Dutch mutant), promotes TRAIL death receptor (DR)‐mediated apoptosis, barrier permeability, and angiogenic impairment within human cerebral ECs. We tested the hypothesis that Hhcy and hypoperfusion exacerbate Aβ‐induced cerebral EC TRAIL DR‐mediated apoptosis, barrier dysfunction, and angiogenesis defects.MethodHuman cerebral microvascular ECs were challenged with AβQ22 and/or homocysteine (Hcy) in the presence/absence of hypoperfusion. Apoptotic mediator expression, caspase activation, and DNA fragmentation were measured to assess apoptosis. BBB protein expression and trans‐endothelial‐electrical‐resistance (TEER) were measured to assess EC barrier integrity. Angiogenesis inhibition and activation assays were utilized to measure EC angiogenic capability.ResultAβQ22 and Hcy challenge independently upregulated EC expression of TRAIL DR‐related apoptotic mediators and caspase activity, and, at certain time‐points, resulted in an additive upregulation of apoptotic mediators and caspase activity. AβQ22, Hcy, and hypoperfusion individually increased DNA fragmentation within cerebral ECs. Combination treatments of AβQ22 and Hcy created an additive effect on DNA fragmentation. Hypoperfusion and AβQ22 independently decreased BBB protein expression and TEER, while an additive decrease was observed with the combined challenges. AβQ22 and Hcy independently decreased angiogenesis progression, with some timepoints revealing an additive decrease with the combination treatment.ConclusionThe presence of CV risk factors seems to exacerbate Aβ induced‐EC apoptosis, barrier dysfunction, and angiogenic impairment, revealing several of the specific molecular mechanism through which amyloidosis and CV risk factors may additively act to produce EC dysfunction and death in AD pathology.

Aims: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by cerebral amyloid β (Aβ) deposition and tau pathology. The AD-mediated degeneration of the brain neuro-signaling pathways, together with a potential 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, neurotrophins, innervation, and amyloidosis is still unknown. Here, we report for the first time that cardiac remodeling, amyloid deposition, and neuro-signaling dysregulation occur in the heart of Tg2576 mice, a widely used model of AD and cerebral amyloidosis. Methods ad Results: Echocardiographic analysis showed significant deterioration of left ventricle function, evidenced by a decline of both ejection fraction and fraction shortening percentage in 12-month-old Tg2576 mice compared to age-matched WT littermates. Tg2576 mice hearts exhibited an accumulation of amyloid aggregates, including Aβ, an increase in interstitial fibrosis and severe cardiac nervous system dysfunction. The transgenic mice also showed a significant decrease in cardiac nerve fiber density, including both adrenergic and regenerating nerve endings. This myocardial denervation was accompanied by a robust reduction in NGF and BDNF protein expression as well as GAP-43 expression (regenerating fibers) in both the brain and heart of Tg2576 mice. Accordingly, cardiomyocytes and neuronal cells challenged with Aβ oligomers showed significant downregulation of BDNF and GAP-43, indicating a causal effect of Aβ on the loss of cardiac neurotrophic function. Conclusions: Overall, this study uncovers possible harmful effects of AD on the heart, revealing cardiac degeneration induced by Aβ through fibrosis and neuro-signaling pathway deregulation for the first time in Tg2576 mice. Our data suggest that AD pathology can cause deleterious effects on the heart, and the peripheral neurotrophic pathway may represent a potential therapeutic target to limit these effects.