VILIP-1 and AD with Psychosis

描述(由申请者提供)：本申请提出了一套完整的研究目标和培训经验，目的是将申请者培养成一名独立的研究人员，进行神经退行性变疾病修改机制的翻译研究。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AD患者(AD-P)相比，AD+P具有认知和功能加速衰退的表型。AD+P认知功能快速下降的背后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β蛋白(A？)寡聚体是AD的主要毒物，它启动LTD(LTDNMDAR)的NMDA受体依赖机制，导致突触丢失。我们实验室一直在研究AD+P如何改变这一过程。最近对AD+P的全基因组关联研究发现，VSNL1基因与AD+P有关。VSNL1编码VILIP-1，是LTDNMDAR所必需的密切相关蛋白亚家族中的一个神经元钙感受器(NCS)。VILIP-1最近也被确定为AD的外周生物标志物。初步数据显示，与对照组相比，在Aü过度生产的小鼠模型中，VILIP-1在大脑皮质中减少，在AD-P受试者死后的背外侧前额叶皮质组织中VILIP-1减少。AD-P组VILIP-1下降幅度大于AD+P组(对照组；AD+P&GT组；AD-P组)。这些发现使我假设VILIP-1蛋白的表达减少是对A？的反应，通过对抗A？启动的LTDNMDAR来降低对可溶性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。我将在一组高度翻译的目标中测试这一假设，结合人类死后研究、啮齿动物模型和原代神经元培养研究。计划中的研究将为我提供有关AD的人体组织研究、先进的定量荧光显微镜、原代神经元培养的实验操作以及RNAi方面的培训。成功完成所提出的目标将指明VILIP-1表达变化的方向；将揭示VILIP-1的表达变化是否改变了Aü对树突棘的影响，并将导致进一步研究VILIP-1在LTD机制中的作用。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 (Aß) 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 Aß 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 Aß, reducing vulnerability to soluble Aß-induced synapse loss by counteracting Aß 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 Aß; will reveal whether altered expression of VILIP-1 modifies the impact of Aß 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.