Investigation of cerebrovascular Notch as a novel modulator of cognitive function

项目摘要 阿尔茨海默氏症(AD)在美国困扰着600多万人，这个数字是 预计到2050年将攀升至近1300万人。有效疗法的发展不仅受到阻碍 由于对阿尔茨海默病发生的致病级联的不完全理解， 确定也能够穿透血脑屏障的疾病修改疗法。渐增 有证据表明，脑血管功能障碍与阿尔茨海默病的发病机制有关，心血管危险因素 由于肥胖和糖尿病使晚发性阿尔茨海默病的风险增加两倍。脑微血管内皮细胞 (BMEC)同时充当中央和外围环境之间的屏障和接口 参与神经发生和神经炎症等过程的调节 血管分泌信号因子。神经发生失调和神经炎症与阿尔茨海默病 病理学以及肥胖症和糖尿病。 Noch蛋白是进化上保守的信号轴的一部分，在 血管功能的发展和维持。在大脑中，内皮细胞Notch(EC-Notch)的调节失调 信号转导导致神经发生和血脑屏障完整性的失调。我们的初步研究已经 研究发现，脑血管内皮细胞中的Notch信号随着年龄的增长而改变，在AD中被破坏，并且抑制 EC-Notch信号对AD引起的认知损害具有保护作用。尽管诺奇是一个很好的描述 血管生成的调节因子，我们没有发现Notch反应的血管形态或密度的明显变化 抑制，提示认知功能的保留可能是血管分泌信号向神经发出的改变所致 细胞。Notch信号的改变是对饮食诱导的反应和调节过程的观察 肥胖(DIO)。因此，响应于DIO的EC-Notch信号的失调可能呈现一种机械性链接 心血管危险因素与AD病理之间的关系。 这项研究将检验EC-Notch信号转导机制参与细胞周期调控失调的假说。 AD和DIO所致认知损害的神经炎症和神经发生。使用诱导式 EC-Notch的遗传抑制，我们将研究它在调控成年海马神经发生和 阿尔茨海默病小鼠模型的神经炎症，目的是识别血管分泌信号因子 调解这些影响。因为Notch信号受代谢的影响，并且能够影响代谢 例如肥胖和胰岛素抵抗，我们将扩大我们的研究以询问EC-Notch的作用 在调节对DIO和胰岛素抵抗的认知损害方面。这些研究将探索EC-Notch 作为家族性和晚发性AD认知功能下降的一种新的常见机制，并审问EC-Notch AS 一种不需要血脑屏障渗透就能影响AD进展的治疗靶点。

Project Summary Alzheimer’s disease (AD) afflicts over 6 million people in the United States, and this number is expected to climb to nearly 13 million by 2050. The development of effective therapeutics is hampered not only by an incomplete understanding of the pathogenic cascades underlying AD development, but the challenges of identifying disease-modifying therapies that are also capable of blood-brain barrier penetrance. Increasing evidence implicates cerebrovascular dysfunction in the pathogenesis of AD, and cardiovascular risk factors such as obesity and diabetes increase the risk of late-onset AD up to two-fold. Brain microvascular endothelial cells (BMEC) act simultaneously as a barrier and interface between the central and peripheral environment and contribute to the regulation of processes such as neurogenesis and neuroinflammation via expression of angiocrine signaling factors. Dysregulation of neurogenesis and neuroinflammation are associated with AD pathology as well as obesity and diabetes. Notch proteins are part of an evolutionarily conserved signaling axis and play critical roles in the development and maintenance of vascular function. In the brain, dysregulation of endothelial Notch (EC-Notch) signaling leads to dysregulation of neurogenesis and blood-brain barrier integrity. Our preliminary studies have found that Notch signaling in the brain endothelium changes with age, is disrupted in AD, and inhibition of EC-Notch signaling is protective against AD-induced cognitive impairment. Although Notch is a well-described regulator of angiogenesis, we did not find overt changes in vascular morphology or density in response to Notch inhibition, suggesting that preservation of cognitive function may result from altered angiocrine signaling to neural cells. Alterations in Notch signaling are observed in response to, and modulate the course of, diet-induced obesity (DIO). Thus, dysregulation of EC-Notch signaling in response to DIO may present a mechanistic link between cardiovascular risk factors and AD pathology. This study will test the hypothesis that EC-Notch signaling contributes to the dysregulation of neuroinflammation and neurogenesis during AD and DIO-induced cognitive impairment. Using inducible genetic inhibition of EC-Notch, we will investigate its role in regulating adult hippocampal neurogenesis and neuroinflammation in a mouse model of AD, with the goal of identifying angiocrine signaling factors which mediate these effects. Because Notch signaling is influenced by, and capable of influencing, metabolic parameters such as obesity and insulin resistance, we will expand our studies to interrogate the role of EC-Notch in mediating cognitive impairment in response to DIO and insulin resistance. These studies will explore EC-Notch as a novel, common mechanism of cognitive decline in familial and late-onset AD and interrogate EC-Notch as a therapeutic target which does not require BBB penetration to exert influence on AD progression.