Neuroprotective Effects of Vascular Endothelial Growth Factor in Alzheimer's Disease

摘要 血管内皮生长因子(VEGF)是一种蛋白质，被认为具有保护作用。 阿尔茨海默病(AD)。脑脊液(CSF)中高水平的血管内皮生长因子与较慢的 认知能力下降和脑萎缩速度减慢。此外，血管内皮生长因子的神经保护作用是 在存在高水平AD神经病理的个体中尤其强烈，提示血管内皮生长因子 可以预防阿尔茨海默病的临床后果。事实上，在治疗AD小鼠的海马体时， 干细胞表达血管内皮生长因子，与AD相关的记忆缺陷被逆转。然而，中国的发展 作为治疗靶点的血管内皮生长因子因其影响的大量生物过程而受到限制 血管内皮生长因子信号。血管内皮生长因子家族由5个配体基因、3个已知的酪氨酸激酶受体基因和2个 调节受体(神经粘连蛋白)基因。这组不同的配体和受体之间的相互作用推动 截然不同的信号级联。这种生物变异提供了一个令人兴奋的机会来审问 通过靶向基因组学和蛋白质组学研究多种血管内皮生长因子途径。这项提案将寻求确定 最强烈地预测神经保护的血管内皮生长因子信号分子，并阐明支持 血管内皮生长因子的有益作用。我们将利用先进的基因组和蛋白质组方法利用人类 样本来自具有良好特征的老龄化纵向队列研究，特别关注基因和 蛋白质在脑组织中的表达。我们的多学科团队处于独特的地位，可以执行这一详细的 利用阿尔茨海默病(RAD)数据库的弹性分析血管内皮生长因子信号 包括对AD的8项大型队列研究的协调和验证的连续弹性指标。在……里面 RAD，我们已经量化了一个人对与以下相关的认知缺陷的弹性程度 AD神经病理，为评价血管内皮细胞生长因子的作用提供了理想的表型。RAD包括 基因型数据(n=3037)、来自脑组织的基因表达数据(n=588)以及访问存储的脑组织 新的蛋白质组分析(n=1433)。这项提案将首先对血管内皮生长因子配体进行全面分析 以及脑组织中的受体基因，以确定哪些基因亚型与韧性最密切相关。第二, 我们将进行详细的蛋白质组分析，其中我们将对所有血管内皮生长因子进行全面测量 配体和受体蛋白形式，包括翻译后修饰，以阐明脑内血管内皮生长因子的作用 蛋白质水平。最后，我们将利用此提案生成的丰富的血管内皮生长因子信号数据来确定 沿着相同的信号通路下降的其他韧性的遗传标记。关于以下方面的知识 最能预测弹性的机制、信号通路和特定形式的血管内皮生长因子 加快血管内皮生长因子信号分子的开发，作为药物干预的靶点。

Abstract Vascular endothelial growth factor (VEGF) is a protein that has been implicated in protection against Alzheimer's disease (AD). High levels of cerebrospinal fluid (CSF) VEGF are associated with slower rates of cognitive decline and slower rates of brain atrophy. Furthermore, the neuroprotective effects of VEGF are particularly strong among individuals who are harboring high levels of AD neuropathology, suggesting VEGF may protect against the clinical consequences of AD. Indeed, when treating the hippocampus of AD mice with stem cells expression VEGF, the memory deficits associated with AD are reversed. Yet, the development of VEGF as a therapeutic target has been limited due to the large number of biological process impacted by VEGF signaling. The VEGF family consists of 5 ligand genes, 3 known tyrosine-kinase receptor genes, and 2 modulating receptor (neuropilins) genes. Interactions between this diverse set of ligands and receptors drive vastly different signaling cascades. Such biological variation provides an exciting opportunity to interrogate the various VEGF pathways through targeted genomics and proteomics. This proposal will seek to identify the VEGF signaling molecules that most strongly predict neuroprotection, and clarify the pathways that underly the beneficial effects of VEGF. We will leverage advanced genomic and proteomic approaches using human samples from well characterized longitudinal cohort studies of aging, with a particular focus on gene and protein expression in brain tissue. Our multi-disciplinary team is uniquely positioned to perform this detailed analysis of VEGF signaling by leveraging the Resilience from Alzheimer's Disease (RAD) database, which includes a harmonized and validated continuous metric of resilience across 8 large cohort studies of AD. In RAD, we have quantified the degree to which an individual is resilient to the cognitive deficits associated with AD neuropathology, providing the ideal phenotype to evaluate the effects of VEGF. The RAD includes genotype data (n=3037), gene expression data from brain tissue (n=588), and access to stored brain tissue for novel proteomic analyses (n=1433). This proposal will first perform a comprehensive analysis of VEGF ligand and receptor genes in brain tissue to identify which gene isoforms mostly strongly relate to resilience. Second, we will perform a detailed proteomic analysis in which we perform comprehensive measurement of all VEGF ligand and receptor proteoforms, including post-translational modifications, to clarify VEGF effects in brain at the protein level. Finally, we will leverage the rich VEGF signaling data generated from this proposal to identify additional genetic markers of resilience that fall along this same signaling pathway. Knowledge about the mechanisms, signaling pathways, and specific forms of VEGF that most strongly predict resilience will accelerate the development of VEGF signaling molecules as targets for pharmacological intervention.