Damage to the brain vasculature significantly contributes to Alzheimer's disease (AD) and dementia. In addition to Cerebral Amyloid Angiopathy (CAA), which is present in more than 90% of AD patients and in many cognitively normal elderly people, chronic cardiovascular (CV) risk factors are also known to impair brain microvascular function. However, the interactive nature of CAA and chronic CV risk factors and the mechanisms through which they contribute to cerebrovascular dysfunction and cognitive decline are poorly understood. Our preliminary work identified molecular mechanisms responsible for amyloid beta (A?)-mediated brain endothelial dysfunction. We propose to clarify the interplay between A? and overexpression/activation of the TRAIL (TNF-related apoptosis inducing ligand) death receptors (DR) DR4 and DR5, unexplored targets of enormous impact for cell stress/death. DR activation triggers mitochondrial dysfunction, with release of pro- apoptotic factors and reactive oxygen species (ROS). Intriguingly, chronic CV risk factors associated with cerebrovascular pathology, such as hypoperfusion, hypertension and hyperhomocysteinemia (HHC), contribute to similar EC death and mitochondrial dysfunction pathways. We will test the hypothesis that chronic CV risk factors, such as hypertension, HHC, and hypoperfusion, synergistically potentiate the effects of cerebrovascular A? in CAA, enhancing TRAIL DR activation and mitochondrial dysfunction in cerebral endothelial cells, and thus leading to neurovascular unit failure in Alzheimer's disease.
In Aim 1, using human cerebral endothelial cells in vitro, we will test the hypothesis that chronic CV risk factors increase endothelial vulnerability to A?, potentiating DR- and mitochondria-mediated pathways. We will analyze the relative contribution of hypoperfusion and HHC to A?-mediated endothelial DR activation, mitochondrial toxicity and BBB permeability through molecular, biochemical and imaging approaches.
In Aim 2, we will test in vivo the hypothesis that chronic CV risk factors potentiate DR- and mitochondria-mediated endothelial dysfunction and increase cerebrovascular amyloid burden in a mouse model of amyloidosis, contributing to neurovascular and cognitive impairment. We will assess these mechanisms in Tg2576 mice exposed to chronic CV risk factors (hypertension or HHC) before or after the development of CAA. We will examine the effects of these stress pathways on BBB dysfunction, microhemorrhages, amyloid deposition, neuroimmune activation, and cognitive function.
In Aim 3 we will Test the hypothesis that manipulations that decrease DR activation (DR silencing) and mitochondrial dysfunction (carbonic anhydrase inhibitors) will prevent or reverse endothelial damage and BBB permeability induced by the combination of A? and chronic cerebrovascular challenges that occur with CV risk. This study will reveal modifiable molecular mechanisms underlying mixed cerebrovascular disease and dementia, which have enormous impact on clinical practice and public health.
Despite the recognized importance of vascular dysfunction for the cognitive outcomes and pathogenesis of Alzheimer's disease, the underlying molecular causes and the relationship of chronic cardiovascular risk factors with cerebrovascular amyloidosis are still unclear. Based on our preliminary studies, which identified death receptors (DRs) and mitochondria as mediators of endothelial cell stress and death triggered by amyloid ? (A?), we hypothesize that chronic cardiovascular risk factors, such as hypertension, hyperhomocysteinemia and cerebral hypoperfusion, synergistically potentiate the effects of cerebrovascular amyloid, enhancing DR activation and mitochondrial dysfunction in cerebral endothelial cells, thus promoting neurovascular failure in Alzheimer's disease. This study aims to a) clarify in vitro the effects of chronic cardiovascular risk factors on the hypothesized mechanisms of A? ? mediated endothelial death and dysfunction; b) analyze in vivo the impact of chronic cardiovascular risk factors on DR- and mitochondria-mediated endothelial dysfunction, amyloidosis and neurodegeneration; and c) examine targeted interventions for mixed cerebrovascular dementias.
