AD and vascular dementia have been traditionally considered separate pathologies; however, recent data suggest that there is an additive or synergistic effect of cerebrovascular damage and AD pathology on cognitive function. The contribution of cerebrovascular change on AD pathogenesis and progression is an understudied area. Studies of human autopsy brains have shown that the severity of cerebrovascular disease is correlated with dementia, most often dementia attributed to AD. However, the underlying mechanism is not clearly understood, and whether cerebrovascular damage is a causal factor in AD pathogenesis or a consequence of AD progression is not known. Understanding the interaction between the pathogenesis of AD and the pathogenesis of cerebrovascular damage may lead to the development of new therapeutics that can target both. Only over the last ten years, however, have we learned that the same signal molecules, e.g., VEGF and BDNF, influence the growth of neuronal and vascular networks. PKC? activates the mRNA- stabilizing protein Hu, which enhances expression of VEGF and BDNF. A decrease in PKC? occurs in neurons and vascular endothelial cells in aged, AD, and in ischemic brains. We hypothesize that AD pathology results from a combination of neurologic and cardiovascular factors.
In Aim 1, we will pathogenesis in neurons and microvasculatures in the human AD and aged-matched control hippocampi from subjects with mixed lesions of hypertension, cardiac disease, and/or cerebrovascular disease. This will provide a thorough understanding of pathogenesis in MV structural changes related to neurons.
In Aim 2, we will assess the effect of PKC? activation on early spatial memory defect in transgenic mouse models of AD with and without cerebrovascular disease. Based on our previous results, we expect to show that cerebrovascular disease and MV changes accelerate neuron loss and AD pathogenesis that is protected with the PKC?-enhanced VEGF & BDNF expression.
In Aim 3, we will determine the effect of PKC? activation on early spatial memory defect in transgenic mouse models of AD with hypertensive heart disease. At the end of this aim, we expect to show that MV change associated with the complex of AD and cardiovascular disease (without cerebrovascular disease) suppresses VEGF & BDNF is prevented with PKC?-specific activators. Understanding the impact of cerebrovascular dysfunction on AD pathophysiology may lead to the development of new therapeutics that addresses both neuronal and vascular pathologies to prevent or slow the progression of the disease to improve the quality of life of affected or at-risk individuals. Our findings may allow for the earlier diagnosis of AD using cerebrovascular biomarkers that can identify at-risk individuals. Importantly, our findings will have broader implications for the treatment of other neurodegenerative diseases and conditions, such as ischemic stroke and traumatic brain injury, in which cerebrovascular inflammation and synaptic loss correlate with cognitive impairment.
We propose to examine whether blood vessel damage is a causal factor in AD pathogenesis or a consequence of AD progression in autopsy-confirmed human Alzheimer?s disease (AD) brains, human neuron and microvascular endothelial cell cultures, and an animal AD model. Our research will establish whether a drug activating protein kinase C ? can prevent damage to the brain blood vessels and neurons, providing key data for further studies of the drug as therapeutic agents that can prevent or slow AD progression and improve quality of life. Understanding the pathogenic events occurring in small blood vessel damage in the brain that contribute to neuron degradation and AD dementia may also help us create new tools that can diagnose AD earlier or identify at-risk patients.
