PILOT: Center for Appalachian Research in Envrionmental Sciences: Bisphenol A: A Trigger of Neurovascular Dysfunction and Cognitive Decline in Alzheimer's Disease?

Current research suggests that Bisphenol A (BPA) found in plastics causes neurodegeneration and cognitive deficits. Our preliminary studies show that BPA triggers neurovascular dysfunction, a condition recognized as both a cause and consequence of the pathological cascade that leads to cognitive decline in Alzheimer¡¦s disease (AD). However, a mechanistic link between BPA, neurovascular function, and AD pathology is unknown. The long-term goal is to identify molecular pathways that trigger neurovascular dysfunction, to determine their contribution to human brain disease, and to exploit these pathways for developing new intervention strategies. The overall objective in this application is to define signaling steps through which BPA impairs neurovascular function and to determine the effect of BPA exposure on learning and memory in AD. Based on our preliminary data, our central hypothesis is that BPA triggers neurovascular dysfunction and accelerates cognitive decline in Alzheimer's disease. Our rationale for this research is that providing proof-of-concept that BPA triggers neurovascular dysfunction and accelerates cognitive decline in AD will establish a framework for future studies focused on intervention strategies to protect the neurovasculature and slow cognitive decline. The central hypothesis will be tested by pursuing three specific aims: 1) Identify the mechanism through which BPA signals neurovascular dysfunction, 2) Determine BPA levels and neurovascular dysfunction in samples from AD patients and 3) Assess the effect of BPA on neurovascular function and cognition in a mouse AD model. Under the first aim, expose isolated mouse brain capillaries to BPA with/without pharmacological antagonists of ERƒÑ and ERƒÒ. We will confirm the results in ERƒÑ and ERƒÒ knockout mice and validate our findings in isolated human brain capillaries. For the second aim, we will conduct a retrospective study using postmortem brain tissue from cognitive normal individuals and AD patients to determine BPA levels, P-gp protein levels, and capillary leakage. For the third aim, we will feed 4-week-old WT and transgenic 5xFAD mice diet with/without BPA. We will determine neurovascular function and cognition after 3, 6 and 9 months. The research proposed in this application is innovative, in our opinion, because it represents a new and substantive departure from the status quo by shifting the focus to a mechanism-driven approach focused on BPA-mediated neurovascular dysfunction, a key feature of AD pathology. The proposed research is significant, because it is expected to provide first proof-of-concept that BPA exposure leads to neurovascular dysfunction and accelerated cognitive decline in AD. Ultimately, such knowledge has the potential to provide evidence for molecular targets that could be utilized to protect neurovascular function.