A Proteomic and Genomic Approach to Understanding Neuropsychiatric Symptoms in Alzheimer's Disease

阿尔茨海默病是一种神经退行性疾病，其特征是蛋白质聚集和 认知能力下降。阿尔茨海默病患者会出现神经精神症状，包括 幻觉和妄想，这也是精神分裂症的特征。有证据表明，女性 阿尔茨海默病患者有更隐蔽的发病，而且许多人有更多 神经精神病学诊断。我们最近发现，在一个子集的蛋白质不溶性增加 精神分裂症患者的尸检脑组织。虽然精神分裂症不是一种神经退行性疾病， 并且没有表现出广泛的神经元丢失，我们的证据表明，就像神经退行性疾病一样， 精神分裂症患者体内可能存在蛋白质聚集。这可能会改变神经元的功能，并对 致病机理。此外，由于阿尔茨海默氏症会出现精神症状，而这些 症状可能发生在认知功能下降之前，一些细胞过程导致蛋白质 阿尔茨海默氏症的聚集率可能与精神分裂症的聚集率相当。有趣的是，我们的数据表明 与男性精神分裂症患者相比，这种聚集在女性患者中可能更常见。我们 假设精神分裂症与蛋白质聚集相关的重叠蛋白质组变化 阿尔茨海默病将涉及基因和蛋白质，从而涉及特定的细胞过程，与 阿尔茨海默病患者神经精神症状和精神病的性别差异。为了测试 在这一假设下，我们建议使用生物信息学方法来分析蛋白质组数据，以便 描述与精神分裂症患者中存在的聚集蛋白相关的细胞过程 控制死后大脑(目标1)。然后，我们将使用生物信息学方法分析蛋白质组数据 为了识别精神分裂症和阿尔茨海默病中存在的潜在重叠聚集蛋白 有精神病的尸检脑(目标2)。最后，我们将使用基因组学方法来确定 AIM 2中确定的一组重叠蛋白中的基因在全基因组关联研究中得到了丰富 治疗与阿尔茨海默病相关的神经精神症状。我们还将执行一个子分析，以 确定这种丰富在女性中是否比男性更明显(目标3)。这项提议可能 提供证据表明精神分裂症中聚集的机制有助于 阿尔茨海默病中出现的神经精神症状，尤其是在女性身上观察到的症状。 对这一问题的探讨可以阐明发病机制，并最终提供治疗靶点。此外， 这项研究计划辅之以综合培训计划，该计划侧重于1)分析方面的培训 生物统计学和计算方法，2)定量蛋白质组和基因组分析，3)解释 蛋白质组和基因组数据及其生物学背景，包括临床和神经生物学方面 所有这些都将有助于候选人发展成为一名独立的调查员。

Alzheimer’s disease is a neurodegenerative disorder characterized by protein aggregation and cognitive decline. Patients with Alzheimer’s disease experience neuropsychiatric symptoms including hallucinations and delusions, which are also characteristic of schizophrenia. Evidence suggests that female patients with Alzheimer’s disease have a more insidious onset of illness, and many have more neuropsychiatric diagnoses. We recently discovered that protein insolubility is increased in a subset of postmortem brains from patients with schizophrenia. While schizophrenia is not a neurodegenerative disorder, and does not exhibit widespread neuronal loss, our evidence suggests that, as in neurodegenerative disorders, protein aggregation may be present in schizophrenia. This could alter the functioning of neurons and contribute to pathogenesis. Furthermore, since Alzheimer’s disease can present with psychiatric symptoms, and these symptoms may occur prior to cognitive decline, some of the cellular processes that cause proteins to aggregate in Alzheimer’s disease may be comparable to those in schizophrenia. Intriguingly, our data suggest that aggregation may occur more often in female compared to male patients with schizophrenia. We hypothesize that the overlapping proteomic changes associated with protein aggregation in schizophrenia and Alzheimer’s disease will implicate genes and proteins, and thus specific cellular processes, associated with the sex differences in neuropsychiatric symptoms and psychosis observed in Alzheimer’s disease. In order to test this hypothesis, we proposed to analyze proteomic data using a bioinformatics approach in order to characterize the cellular processes associated with aggregated proteins present in schizophrenia versus control postmortem brains (Aim 1). We will then analyze proteomic data using a bioinformatics approach in order to identify potentially overlapping aggregated proteins present in schizophrenia versus Alzheimer’s postmortem brain with psychosis (Aim 2). Finally, we will use a genomics approach to determine whether the genes from the set of overlapping proteins identified in Aim 2 are enriched in genome wide association studies for neuropsychiatric symptoms related to Alzheimer’s disease. We will also perform a sub analysis to determine whether this enrichment is more predominant in women than men (Aim 3). This proposal may provide evidence that the mechanisms responsible for aggregation in schizophrenia contribute to the neuropsychiatric symptoms that occur in Alzheimer’s disease, particularly those observed in women. Exploration into this subject could elucidate pathogenesis and ultimately provide therapeutic targets. Further, this research plan is complemented by an integrated training plan that focuses on training in 1) analytical biostatistics and computational methods, 2) quantitative proteomic and genomic analysis and 3) interpretation of proteomic and genomic data and its biological context, including the clinical and neurobiological aspects of AD, all of which will facilitate the candidate’s development into an independent investigator.