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.

识别阿尔茨海默病 (AD) 的环境风险因素对于缓解阿尔茨海默病 (AD) 认知能力下降至关重要 人类。我们提供的第一个证据表明，内分泌干扰双酚 (BP) 具有临床相关性 AD 的环境危险因素。人类接触 BPA 以及双酚类似物 BPF 和 BPS 是不可避免的 由于它们在环境中无处不在。我们的数据显示 BPA 会触发血脑屏障 功能障碍和认知障碍是 AD 的两个标志，表明环境血压是一个关键因素 AD 风险因素未被充分认识。 BP 引起的屏障功能障碍的主要特征包括：1） β 淀粉样蛋白 (Ab) 清除转运蛋白 P-糖蛋白 (P-gp) 和 2) 屏障渗漏的发展。这两个 多种因素导致病理级联反应，导致 AD 认知能力下降。虽然有证据表明 BP暴露导致屏障功能失调，这种现象背后的机制尚不清楚，关键是 没有连接BP和AD的机制数据，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，我们解决了这一未满足的关键需求，并建议定义以下内容的相关性： BP 作为 AD 的危险因素。我们在本提案中的目标是定义 BP 诱导的信号传导步骤 屏障功能障碍并导致 AD 认知能力下降。根据初步数据，我们的中心假设 BP 会导致 AD 模型中的屏障功能障碍，增加 Ab 水平并加剧认知能力下降。我们的 这项研究的基本原理是确定 BP 诱导屏障功能障碍的机制 加剧认知障碍将证明内分泌干扰物是一种环境因素 AD 的危险因素。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 中的血压水平、屏障功能障碍和认知 患者与 CNI 相比。 3) 制定修复血压引起的屏障功能障碍和减缓认知的策略 体内衰退。在目标 1 中，我们将确定导致 BP 诱导的 P-gp 损失和屏障渗漏的信号传导步骤。 分离的小鼠脑毛细血管，我们将在 KO 小鼠的毛细血管和分离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 来自认知正常个体、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 信号传导以减轻屏障功能障碍，并评估该策略对减缓认知能力的益处 小鼠 AD 模型中体内的下降。拟议的研究具有创新性，因为它代表了实质性的 摆脱现状，转向机制驱动的方法，重点关注内分泌的影响 干扰物对 AD 的屏障功能和认知有影响。拟议的研究意义重大，因为它 预计将改变我们对环境风险因素对 AD 重要性的理解。