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

双酚引起的阿尔茨海默氏病血脑屏障功能障碍

• 批准号: 10713025
• 负责人: Anika M.S. Hartz
• 金额: $ 73.8万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713025
• 关键词: ABCB1 gene; Abeta clearance; Address; Aging; Air; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Beverages; Blood brain barrier dysfunction; Blood capillaries; Brain; Characteristics; Cognition; Cognitive; Cognitive deficits; Data; Development; Dust; Endocrine Disruptors; Endocrine disruption; Environment; Environmental Impact; Environmental Risk Factor; Estrogen Receptor beta; Exposure to; Extravasation; FDA approved; Food; Fulvestrant; Functional disorder; Health; Human; Impaired cognition; Impairment; Individual; Knockout Mice; Knowledge; Link; Medical Device; Mission; Monkeys; Mus; National Institute of Environmental Health Sciences; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Outcome; Oxidative Stress; PIK3CG gene; Paper; Pathologic; Pharmaceutical Preparations; Plastics; Public Health; Research; Risk Factors; Rodent; Sampling; Signal Transduction; Soil; Testing; Time; Tissue Sample; Work; analog; bisphenol A; burden of illness; cerebral capillary; clinically relevant; cognitive enhancement; drinking water; exposed human population; human tissue; in vivo; in vivo Model; innovation; neuron development; pre-clinical; repaired

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.

确定阿尔茨海默病(AD)的环境危险因素对于缓解认知能力下降至关重要 人类。我们提供的第一个证据表明内分泌干扰性双酚(BP)与临床相关。 AD的环境风险因素。人类接触双酚A及其类似物BPF和BPS是不可避免的 因为它们在环境中无处不在。我们的数据显示双酚A会触发血脑屏障 功能障碍和认知障碍，这两个AD的标志，表明环境BP是一个关键的 未被认识到的AD风险因素。BP诱导的屏障功能障碍的主要特征包括：1) 淀粉样β蛋白(Ab)清除转运体P-糖蛋白(P-gp)；2)屏障渗漏。这两者都是 这些因素导致了导致AD认知功能下降的病理性级联反应。虽然有证据表明 BP暴露会导致功能障碍，这种现象背后的机制尚不清楚，关键是 没有将BP和AD联系起来的机械性数据，这阻碍了我们对环境风险的理解 AD的影响因素。在本申请中，我们解决了这一关键的未得到满足的需求，并建议定义 BPS是AD的危险因素。我们在这个提案中的目标是定义BPS诱导的信令步骤 屏障功能障碍是AD认知功能下降的原因之一。根据初步数据，我们的中心假设 在AD模型中，BP导致屏障功能障碍，增加抗体水平，并增强认知能力下降。我们的 这项研究的基本原理是确定BP导致屏障功能障碍和 加剧认知障碍将提供内分泌干扰物是环境因素的概念证明 AD的危险因素。这一假说将通过追求三个具体目标来检验：1)确定机制 对BP引起的屏障功能障碍负责。2)测定AD患者的血压水平、屏障功能障碍和认知功能 患者与CNI相比。3)制定一种策略来修复BP导致的屏障功能障碍和认知减慢 在体内呈下降趋势。在目标1中，我们将确定导致BP诱导的P-gp丢失和屏障泄漏的信号步骤 分离的小鼠脑毛细血管，我们将在KO小鼠和分离的小鼠的毛细血管中验证这些发现 人脑毛细血管。在目标2中，我们将确定血压水平和屏障功能障碍的程度 来自认知正常人、临床前AD、MCI和AD患者的人体组织样本。在《目标3》中，我们将 阻断BP信号以缓解屏障功能障碍，并评估该策略在减缓认知能力方面的益处 在小鼠AD模型中的体内下降。拟议的研究具有创新性，因为它代表了一项实质性的 改变现状，转向注重内分泌影响的机制驱动方法 干扰物对阿尔茨海默病的屏障功能和认知功能有一定影响。这项拟议的研究具有重要意义，因为它 预计将使我们对环境风险因素对AD的重要性的理解发生范式转变。