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：约40-60%的阿尔茨海默病（AD）患者会出现精神病症状 精神病，AD+P）。许多研究发现AD+P表型与更快速的 认知功能下降的程度高于无精神病的AD受试者（AD-P）。目前，经验开发的治疗方法， AD中的精神病疗效有限，不能改变更快的疾病进展，并且与 严重的毒性，包括过度死亡。由于AD患者精神病的年发病率仅为~ 10%， 如果能够确定复原力因素，就有机会进行干预，以预防精神病发作。 多项脑成像研究表明，相对于AD+P，AD-P受试者保留了 皮质突触功能的指标，特别是在背外侧前额叶皮质（DLPFC）。我们最近 在患者和模型系统中的遗传学和蛋白质组学发现已经集中在一种可能的机制上， 解释AD-P中的这种突触弹性：DLPFC中突触后密度（PSD）蛋白水平的保留。 首先，在轻度至中度AD的DLPFC灰质匀浆中使用靶向质谱法（MS） 受试者中，我们发现AD-P受试者中典型PSD蛋白的匀浆水平相对于 AD+P和对照受试者。第二，我们发现并独立证实了一种多基因保护， 针对AD中的精神病，其包括与TOM 1 L2的DLPFC表达降低相关的等位基因。 TOM 1 L2是一种衔接蛋白，通过肌动蛋白内吞促进突触蛋白的降解。 贩卖人口最后，在Aβ过度产生的APPswe/PSEN 1dE 9小鼠模型中，我们发现， Kalrn，一种调节内吞运输的Rac 1/RhoA鸟嘌呤核苷酸交换因子， 皮质匀浆中的典型PSD蛋白水平，在PSD富集物中保持这些蛋白水平， 并防止精神病相关行为。因此我们假设：对精神病发作的恢复力 在AD中，由于PSD富集物中蛋白质水平的保持， PSD蛋白的降解，并可用于识别新的治疗。我们将检验这一假设 目的1）确定PSD蛋白质组改变和基因-蛋白质相互作用是否相关 目的2）测试Tom 112减少对小鼠突触蛋白质组的影响 目的3）利用计算化学基因组学技术鉴定诱导突触蛋白质组的药物 补偿，其赋予对AD+P的恢复力，提供合理的预防和/或治疗。上述 aims受益于紧密集成和利用多个具有突触病理学专业知识的PI， 精神病（Sweet），AD的神经病理学（Kofler），以及计算在新治疗中的应用 发现（Wang）。完成后，我们将描绘出突触蛋白补偿相关的 与AD中精神病的恢复有关，并发现导致产生突触恢复的化合物， 未来研究中的未来测试。