Bisphenol-Induced Blood-Brain Barrier Dysfunction in Alzheimer’s Disease

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Identifying environmental risk factors for Alzheimer’s Disease (AD) is critical to mitigate cognitive decline in humans. We provide first evidence showing that endocrine disrupting bisphenols (BP) are clinically relevant environmental risk factors for AD. Human exposure to BPA and the bisphenol analogs BPF and BPS is inevitable due to their ubiquitous presence in the environment. Our data show that BPA triggers blood-brain barrier dysfunction and cognitive impairment, both hallmarks of AD, indicating that environmental BPs are a critical yet underrecognized AD risk factor. Key characteristics of BP-induced barrier dysfunction include: 1) loss of the amyloid-beta (Ab) clearance transporter P-glycoprotein (P-gp) and 2) development of barrier leakage. Both these factors contribute to a pathological cascade that leads to cognitive decline in AD. While there is evidence that BP exposure results in a dysfunctional barrier, the mechanism underlying this phenomenon is unknown, and key mechanistic data linking BPs and AD are not available, which hinders our understanding of environmental risk factors for AD. In this application, we address this critical unmet need and propose to define the relevance of BPs as risk factors for AD. Our objective in this proposal is to define signaling steps through which BPs induce barrier dysfunction and contribute to cognitive decline in AD. Based on preliminary data, our central hypothesis is that BPs induce barrier dysfunction, increase Ab levels, and enhance cognitive decline in an AD model. Our rationale for this research is that identifying the mechanism through which BPs induce barrier dysfunction and exacerbate cognitive impairment will provide proof-of-concept that endocrine disruptors are an environmental risk factor for AD. The hypothesis will be tested by pursuing three specific aims: 1) Identify the mechanism responsible for BP-induced barrier dysfunction. 2) Determine BP levels, barrier dysfunction, and cognition in AD patients compared to CNI. 3) Develop a strategy to repair BP-induced barrier dysfunction and slow cognitive decline in vivo. In Aim 1, we will identify signaling steps that lead to BP-induced P-gp loss and barrier leakage in isolated mouse brain capillaries, and we will verify these findings in capillaries from KO mice and in isolated human brain capillaries. In Aim 2, we will determine BP levels and the degree of barrier dysfunction BP levels in human tissue samples from cognitive normal individuals, preclinical AD, MCI and AD patients. In Aim 3, we will block BP signaling to mitigate barrier dysfunction and evaluate the benefit of this strategy on slowing cognitive decline in vivo in a mouse AD model. The proposed research is innovative because it represents a substantive departure from the status quo by shifting to a mechanism-driven approach focused on the impact endocrine disruptors have on barrier function and cognition in AD. The proposed research is significant because it is expected to create a paradigm shift in our understanding of the importance of environmental risk factors for AD.