Synaptic Resilience to Psychosis in Alzheimer Disease

阿尔茨海默病的突触对精神病的抵抗力

基本信息

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
项目类别：
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&apos 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

项目摘要

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：大约 40-60% 的阿尔茨海默病（AD 伴有精神病，AD+P) 大量研究发现 AD+P 表型与更快的速度相关。目前根据经验开发的治疗方法比没有精神病的 AD 受试者 (AD-P) 认知能力下降。 AD 中的精神病的疗效有限，不会改变更快的疾病进展，并且与严重的毒性，包括过高的死亡率因为 AD 中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的发作。多项脑成像研究表明，相对于 AD+P，患有 AD-P 的受试者保留了皮质突触功能指数，特别是背外侧前额叶皮层（DLPFC）。患者和模型系统的遗传和蛋白质组学发现已趋同于一种可能的机制解释 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 (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其次，我们鉴定并独立证实了多基因保护。对抗 AD 中的精神病，其中包括与 TOM1L2 DLPFC 表达减少相关的等位基因。 TOM1L2 是一种接头蛋白，可通过基于肌动蛋白的内吞作用促进突触蛋白的降解最后，在 Aβ 过量产生的 APPswe/PSEN1dE9 小鼠模型中，我们发现 Aβ 的减少。 Kalrn，一种调节内吞运输的 Rac1/RhoA 鸟嘌呤核苷酸交换因子，升高皮质匀浆中的典型 PSD 蛋白水平，在 PSD 富集中保留了这些蛋白的水平，并防止与精神病相关的行为，因此我们欺负：对精神病发作的恢复力。在 AD 中，由于减少了 PSD 富集中的蛋白质水平，因此可以保留蛋白质水平 PSD 蛋白可降解，可用于识别新的治疗方法我们将测试这一假设。三个目标：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 的恢复能力；目标 2) 测试 Tom1l2 减少对小鼠突触蛋白质组的影响模型，以及；目标 3) 使用计算化学基因组学来鉴定诱导突触蛋白质组的药物补偿赋予 AD+P 弹性，提供合理的预防和/或治疗。目标受益于多个 PI 的紧密集成和利用，这些 PI 具有突触病理学方面的专业知识精神病（Sweet）、AD 的神经病理学（Kofler）以及计算在新型治疗中的应用发现（Wang）完成后，我们将描述相关的突触蛋白补偿。具有对 AD 精神病的恢复力，并发现了可产生突触恢复力的化合物未来研究中的未来测试。