Synaptic Resilience to Psychosis in Alzheimer Disease

阿尔茨海默病的突触对精神病的抵抗力

• 批准号: 9975225
• 负责人: Julia K Kofler
• 金额: $ 59万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-25 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975225
• 关键词: Actins; Adaptor Signaling Protein; Alleles; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Behavior; Biological Assay; Biological Models; Brain; Brain imaging; Caregiver Burden; Cerebral cortex; Collaborations; Databases; Delusions; Deterioration; Disease; Disease Progression; Drug Combinations; Elderly; Excess Mortality; Financial compensation; Future; Gene Proteins; Genetic; Genetic Variation; Genotype; Grant; Guanine Nucleotide Exchange Factors; Hallucinations; Impaired cognition; Incidence; Individual; Link; Mass Spectrum Analysis; Mus; Outcome; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Prefrontal Cortex; Prevention; Proteins; Proteome; Proteomics; Psychotic Disorders; Research Personnel; Severities; Synapses; Synaptosomes; Testing; Tissues; Toxic effect; base; causal model; cohort; density; disability; drug discovery; genetic association; gray matter; imaging study; indexing; innovation; mortality; mouse model; neuropathology; novel; novel therapeutics; postsynaptic; postsynaptic density protein; preservation; prevent; protein degradation; protein profiling; psychotic symptoms; resilience; screening; synaptic function; trafficking; transcriptome

PROJECT SUMMARY: Psychotic symptoms occur in ~ 40-60% of individuals with Alzheimer Disease (AD with psychosis, AD+P). Numerous studies have found that the AD+P phenotype is associated with more rapid cognitive decline than AD subjects without psychosis (AD-P). Current, empirically developed, treatments for psychosis in AD have limited efficacy, do not alter the more rapid disease progression, and are associated with substantial toxicity, including excess mortality. Because the annual incidence of psychosis in AD is only ~ 10%, there is a window of opportunity to intervene to prevent psychosis onset if resilience factors can be identified. Multiple brain imaging studies have shown that relative to AD+P, subjects with AD-P have preserved indices of cortical synaptic function, especially in the dorsolateral prefrontal cortex (DLPFC). Our recent genetic and proteomic findings in patients and model systems have converged on a possible mechanism to explain this synaptic resilience in AD-P: Preservation of postsynaptic density (PSD) protein levels in DLPFC. First, using targeted mass spectrometry (MS) in DLPFC grey matter homogenates from mild to moderate AD subjects, we found a robust increase in homogenate levels of canonical PSD proteins in AD-P subjects relative to both AD+P and Control subjects. Second, we identified and independently confirmed a polygenic protection against psychosis in AD which included an allele associated with reduced DLPFC expression of TOM1L2. TOM1L2 is an adaptor protein that facilitates degradation of synaptic proteins via actin-based endocytic trafficking. Finally, in the APPswe/PSEN1dE9 mouse model of Aβ overproduction, we found that reduction of Kalrn, a Rac1/RhoA guanine nucleotide exchange factor that regulates endocytic trafficking, elevated canonical PSD protein levels in cortical homogenates, preserved these proteins' levels in PSD enrichments, and protected against psychosis-associated behaviors. We thus hypothesize: resilience to psychosis onset in AD is conferred by preservation of protein levels in PSD enrichments, due to reduced trafficking of PSD proteins for degradation, and can be used to identify novel therapeutics. We will test this hypothesis in three Aims: Aim 1) To determine if PSD proteome alterations and gene-protein interactions are associated with resilience to AD+P; Aim 2) To test the effect of reduction in Tom1l2 on the synaptic proteome in a mouse model, and; Aim 3) To use computational chemogenomics to identify drugs that induce synaptic proteome compensations which confer resilience to AD+P, providing for rational prevention and/or treatment. The above aims benefit from the tight integration and leveraging of Multiple PIs with expertise in the synaptic pathology of psychosis (Sweet), the neuropathology of AD (Kofler), and the use of computation for novel therapeutic discovery (Wang). Upon completion, we will have delineated the synaptic protein compensations associated with resilience to psychosis in AD and discovered leads to compounds that generate synaptic resilience for future testing in future studies.

项目摘要：精神病症状发生在约40-60％的阿尔茨海默氏病（AD） 精神病，AD+P）。大量研究发现AD+P表型与更快有关 认知能力下降比没有精神病的AD受试者（AD-P）。目前，经验开发的治疗方法 AD中的精神病的效率有限，不要改变疾病的进展更快，并且与 实质性毒性，包括过量死亡率。因为AD中精神病的年发病率仅为10％，所以 如果可以识别出弹性因素，则有机会进行干预以防止精神病的发作。 多个脑成像研究表明，相对于AD+P，AD-P受试者保留了 皮质突触功能的指标，尤其是在背侧前额叶皮层（DLPFC）中。我们的最新消息 患者和模型系统中的遗传和蛋白质组学发现已将可能的机制转化为 解释AD-P中的这种合成弹性：DLPFC中突触后密度（PSD）蛋白水平的保存。 首先，使用来自轻度至中度AD的DLPFC灰质匀浆中的靶向质谱法（MS） 受试者，我们发现在AD-P受试者中，均质的均匀水平的匀浆水平相对 对AD+P和控制受试者。其次，我们确定并独立确认了多基因保护 AD中的精神病，其中包括与TOM1L2的DLPFC表达降低相关的等位基因。 TOM1L2是一种衔接蛋白，可通过基于肌动蛋白的内吞促进突触蛋白的降解 贩运。最后，在Appswe/psen1de9小鼠Aβ过量生产的模型中，我们发现还原 Kalrn是一种调节内吞贩运的Rac1/RAC1/RAC1/RHOA GUANINE核丁基交换因子，升高 皮质匀浆中的规范PSD蛋白水平，保留了这些蛋白质水平的PSD富集水平， 并保护与精神病相关的行为。因此，我们假设：对精神病发作的韧性 在PSD富集中蛋白质水平的制备赋予了AD中的AD PSD蛋白用于降解，可用于鉴定新的疗法。我们将检验这个假设 在三个目标中：目标1）确定PSD蛋白质组改变和基因 - 蛋白质相互作用是否相关 具有对AD+P的韧性；目标2）测试TOM1L2减少对小鼠突触蛋白质组的影响 模型，并且；目标3）使用计算化学组学鉴定诱导突触蛋白质组的药物 赔偿哪些会议的弹性对AD+P，提供了理性的预防和/或治疗。以上 目标受益于多个PI的紧密整合和利用与在 精神病（甜），AD的神经病理学（Kofler）和新型疗法的使用 发现（王）。完成后，我们将描述与突触蛋白补偿相关的补偿 在AD中对精神病的韧性并发现的可产生突触弹性的化合物 未来研究的未来测试。