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; 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.

确定阿尔茨海默氏病（AD）的环境风险因素对于减轻认知能力下降至关重要 人类。我们提供了第一个证据，表明内分泌干扰双酚（BP）在临床上是相关的 AD的环境风险因素。人类接触BPA和Bisphenol类似物BPF和BPS是不可避免的 由于它们在环境中的存在。我们的数据表明，BPA触发血脑屏障 功能障碍和认知障碍，这是AD的两个标志，表明环境BP是至关重要的 未公认的广告风险因素。 BP引起的屏障功能障碍的关键特征包括：1） 淀粉样蛋白β（AB）清除转运蛋白P-糖蛋白（P-GP）和2）屏障泄漏的发展。这两个 因素有助于导致AD认知能力下降的病理级联。虽然有证据表明 BP暴露会导致功能失调的障碍，此现象的基础机制尚不清楚，关键 链接BP和AD的机械数据不可用，这阻碍了我们对环境风险的理解 AD的因素。在此应用程序中，我们解决了这个关键的未满足需求和建议，以定义 BP作为AD的风险因素。我们在此提案中的目标是定义BPS影响的信号步骤 障碍功能障碍并导致AD认知能力下降。基于初步数据，我们的中心假设 BP会诱导屏障功能障碍，增加AB水平并增强AD模型的认知下降。我们的 这项研究的理由是确定BP诱导屏障功能障碍和 加剧认知障碍将提供概念概念，表明内分泌干扰物是一种环境 AD的风险因素。该假设将通过追求三个具体目标来检验：1）确定机制 负责BP引起的屏障功能障碍。 2）确定AD中的BP水平，屏障功能障碍和认知 患者与CNI相比。 3）制定一种修复BP引起的障碍功能障碍和慢速认知的策略 体内下降。在AIM 1中，我们将确定导致BP引起的P-gp丢失和屏障泄漏的信号步骤 孤立的小鼠脑毛细血管，我们将在KO小鼠和孤立的毛细血管中验证这些发现 人脑毛细血管。在AIM 2中，我们将确定BP水平和屏障功能障碍BP水平的程度 来自认知正常个体，临床前AD，MCI和AD患者的人体组织样本。在AIM 3中，我们将 阻止BP信号来减轻屏障功能障碍并评估该策略在减慢认知方面的好处 鼠标广告模型中的体内下降。拟议的研究具有创新性，因为它代表了实质性的 通过转移到以机构为驱动的方法，侧重于内分泌 破坏者在AD中具有障碍功能和认知。拟议的研究很重要，因为它是 预计我们对环境风险因素对AD的重要性的理解会产生范式转变。