VILIP-1 and AD with Psychosis

描述（由申请人提供）：本申请提出了一套完整的研究目标和培训经验，目的是培养申请人成为一名独立的研究人员，从事神经变性疾病改变机制的转化研究。阿尔茨海默病伴精神病（AD+P）发生在大约一半的阿尔茨海默病患者中，与无精神病的阿尔茨海默病患者（AD-P）相比，其认知和功能衰退加速。AD+P患者认知能力快速下降的潜在原因是新皮质突触病理的增加。越来越多的证据表明可溶性淀粉样蛋白（A¿）寡聚物是AD的主要毒性物质，它启动NMDA受体依赖的LTD （LTDNMDAR）机制，导致突触丢失。我们的实验室一直在研究如何在AD+P中改变这一过程。最近对AD+P的全基因组关联研究发现了VSNL1基因与AD+P的关联。VSNL1编码VILIP-1，这是LTDNMDAR所必需的密切相关蛋白亚家族中的神经元钙传感器（NCS）。VILIP-1最近也被确定为AD的外周生物标志物。初步数据表明，在a¿过量产生的小鼠模型中，与对照组相比，AD-P受试者死后背外侧前额叶皮层组织中的VILIP-1减少。AD-P组VILIP-1的下降幅度大于AD+P组（对照>AD+P>AD-P）。这些发现使我假设VILIP-1蛋白表达在A¿的反应中降低，通过抵消A¿引发的LTDNMDAR，降低了可溶性A¿诱导的突触丢失的易感性，并且这种神经保护作用在AD+P中减弱。我将在一系列高度可翻译的目标中检验这一假设，这些目标结合了人类尸检、啮齿动物模型和初级神经元培养研究。计划中的研究将为我提供阿尔茨海默病的人体组织研究、高级定量荧光显微镜、原代神经元培养的实验操作和RNAi方面的培训。所提出的Aims的成功完成将指示A¿存在下VILIP-1表达改变的方向；将揭示VILIP-1表达的改变是否会改变A¿对树突棘的影响；将进一步研究VILIP-1对LTD机制的影响。最终，了解VILIP-1在AD+P中的机制将指导未来的治疗策略，以改善患有阿尔茨海默病的美国老年人的健康和福祉。

DESCRIPTION (provided by applicant): This application proposes an integrated set of research aims and training experiences with the goal of fostering the applicant's development into an independent researcher conducting translational studies of disease modifying mechanisms in neurodegeneration. Alzheimer disease with psychosis (AD+P) occurs in approximately half of all Alzheimer disease subjects and identifies a phenotype with accelerated cognitive and functional decline in comparison to AD subjects without psychosis (AD-P). Underlying the rapid cognitive decline of AD+P is increased neocortical synaptic pathology. A growing pool of evidence implicates soluble amyloid beta (A¿) oligomers as a primary toxic agent in AD, which initiates NMDA receptor dependent mechanisms of LTD (LTDNMDAR), resulting in synapse loss. Our lab has been conducting investigations of how this process may be modified in AD+P. Recent genome wide association study of AD+P identified an association of the VSNL1 gene with AD+P. VSNL1 encodes VILIP-1, a neuronal calcium sensor (NCS) in a subfamily of closely related proteins which are necessary for LTDNMDAR. VILIP-1 has also recently been identified as a peripheral biomarker of AD. Preliminary data indicates that VILIP-1 is reduced in the cortex in a mouse model of A¿ overproduction, and in post-mortem dorsolateral prefrontal cortex tissue from AD-P subjects compared to control subjects. The decrease in VILIP-1 was greater in AD-P than in AD+P subjects (control>AD+P>AD-P). These findings have led me to hypothesize that VILIP-1 protein expression is decreased in response to A¿, reducing vulnerability to soluble A¿-induced synapse loss by counteracting A¿ initiated LTDNMDAR, and this neuroprotective effect is attenuated in AD+P. I will test this hypothesis in a set of highly translational aims combining human post-mortem, rodent model, and primary neuronal culture studies. The planned studies will provide me training in human tissue studies of AD, advanced quantitative fluorescence microscopy, experimental manipulation of primary neuronal cultures, and RNAi. Successful completion of the proposed Aims will indicate the direction of VILIP-1 expression alteration in the presence of A¿; will reveal whether altered expression of VILIP-1 modifies the impact of A¿ on dendritic spines, and; will lead to further studies investigating of the effects of VILIP-1 on mechanisms of LTD. Ultimately, understanding the mechanisms of VILIP-1 in AD+P will direct future therapeutic strategies to improve the health and well- being of older Americans suffering from Alzheimer disease. PUBLIC HEALTH RELEVANCE: Psychosis in Alzheimer's disease (AD+P) is a highly heritable phenotype of AD that occurs in 40-60% of the estimated 5.2 million individuals with AD in the United States of America. AD+P presents with an accelerated trajectory of cognitive and functional decline, which is associated with greater neocortical synaptic pathology. Current treatments for AD+P have limited efficacy and are associated with substantial toxicity, resulting in increased risk of death. Understanding distinct causal neurobiological factors, like the role of VILIP-1 in AD+P, will lead to improved therapeutic strategies and profoundly impact patients, caregivers, and society as a whole.