Molecular Mechanisms Underlying Behavioral and Psychological Symptoms in Alzheimers Disease

阿尔茨海默病行为和心理症状的分子机制

• 批准号: 10452490
• 负责人: Hongxin Dong
• 金额: $ 67.36万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452490
• 关键词: AD transgenic mice; APP-PS1; Affect; Affective; Aggressive behavior; Agitation; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid deposition; Animal Model; Animals; Anterior; Anxiety; Appearance; Area; Autopsy; Behavior; Behavior Therapy; Behavioral; Behavioral Model; Behavioral Symptoms; Biochemical; Bioinformatics; Brain; CRISPR/Cas technology; Candidate Disease Gene; Caregivers; Clinical assessments; Collaborations; Computer software; Data; Databases; Delusions; Dementia; Development; Disease; Disease Progression; Disinhibition; Distress; Elements; Etiology; Frequencies; Future; Gene Expression; Gene Expression Profile; Genes; Goals; Hallucinations; Human; Hyperactivity; Impaired cognition; Individual; Institutionalization; Intervention; Investigation; Lead; Link; Literature; Mediating; Memory Loss; Memory impairment; Mental Depression; Methods; Modeling; Molecular; Mouse Strains; Mus; Online Mendelian Inheritance In Man; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Play; Prefrontal Cortex; Prevention strategy; Proteomics; Psychoses; Quality of life; Research; Research Personnel; Risk; Role; Severities; Signal Pathway; Symptoms; Syndrome; Testing; Tg2576; Therapeutic; Therapeutic Intervention; Time trend; Tissues; Transgenic Mice; Viral; Western Blotting; Work; affective disturbance; analog; base; cingulate cortex; dysphoria; genetic manipulation; human study; human subject; human tissue; immunocytochemistry; mouse model; neuron loss; neuronal circuitry; neuropsychiatry; novel; novel therapeutic intervention; parity; prevent; psychological symptom; sex; symptom cluster; transcriptome sequencing; translational pipeline; treatment strategy

Summary Over 90% of Alzheimer's disease (AD) patients suffer from behavioral and psychological symptoms of dementia (BPSD) including agitation, aggression, depression, apathy and psychosis. BPSD can present at almost any stage of AD, and in some patients, these symptoms can even appear before dementia develops. The severity of BPSD increases significantly with disease progression, and affects the quality of life of both patients and their caregivers. In many patients, BPSD is the main reason for institutionalization. However, the mechanisms underlying BPSD are not known, and there is no specific treatment strategy available. Although BPSD presents differently in each patient, the presence of certain symptoms in a patient make the co-occurrence of other symptoms more likely. In an ongoing collaboration with Rush Alzheimer's Disease Center, we have developed a method for clustering the symptoms of BPSD into four domains (affective, hyperactivity/disinhibition, psychosis and apathy). Based on these domains, we then conducted an RNA-seq and found different gene expression profiles in AD patients with and without BPSD. This evidence supports the notion that distinct molecular pathways may be involved in the appearance of BPSD. In this proposal, we hypothesize that individual BPSD domains in patients with AD are due to definable perturbations in molecular pathways and that these pathways can be analogized in AD mouse models, allowing for a causal investigation of the relationship between specific pathway alterations and domain behaviors. We will test this hypothesis through both human study and animal work. For the human study, 1) we will expand on our behavioral analyses by increasing subjects for pre-mortem clinical assessments and defining BPSD trends over time in AD patients. 2) Within each behavioral domain, we will employ RNA-seq to investigate gene expression patterns in different brain sub-regions that are unique to each BPSD domain and the gene expression pattern will be compared across normal, MCI and AD subjects. 3) Finally, we will identify which pathways are most clearly associated with each of the BPSD domains using bioinformatics and biochemical analyses. For the animal model work, 1) we will characterize how mouse behaviors analogous to human BPSD symptoms evolve during AD-like neuropathgenesis progression 2) We will identify the most promising molecular candidates for intervention from our RNA-seq findings using these AD/BPSD models. 3) Finally, we will determine whether altering these pathways leads to changes in BPSD-like behavior using virally mediated genetic manipulations (AAV9/CRISPR-Cas9). Overall, this project will establish a translational pipeline by associating BPSD symptom domains with molecular alterations in human AD patients, and by demonstrating that manipulations of these pathways can cause BPSD-like behaviors in transgenic mouse models of AD. These data-driven approaches will lead to a better understanding of the molecular mechanisms that underlie BPSD in AD and potentially identify novel targets for future therapeutic interventions.

摘要 超过90%的阿尔茨海默病(AD)患者患有 痴呆症(BPSD)包括情绪激动、攻击性、抑郁、冷漠和精神病。BPSD可以在 几乎AD的任何阶段，在一些患者中，这些症状甚至可以在痴呆之前出现 发展起来。随着疾病的进展，bpsd的严重程度显著增加，并影响生活质量。 两个病人和他们的照顾者。在许多患者中，BPSD是住院的主要原因。 然而，bpsd的发病机制尚不清楚，也没有具体的治疗策略。 可用。尽管BPSD在每个患者中表现不同，但患者中某些症状的出现 使其他症状更有可能同时出现。在与拉什阿尔茨海默氏症的持续合作中 疾病中心，我们开发了一种方法，将BPSD的症状分类为四个领域 (情感、多动/去抑制、精神病和冷漠)。基于这些领域，我们随后进行了一项 RNA-seq，并发现患有和不患有BPSD的AD患者的基因表达谱不同。这一证据 支持不同的分子途径可能与BPSD的出现有关的观点。在这 建议，我们假设AD患者中的单个BPSD域是由于可定义的扰动 在分子途径中，这些途径可以在AD小鼠模型中类比，从而允许因果关系 研究特定途径改变与结构域行为之间的关系。我们将对此进行测试 通过人类研究和动物工作提出的假设。对于人体研究，1)我们将扩展我们的 通过增加死前临床评估和确定BPSD趋势的受试者进行行为分析 随着时间的推移，阿尔茨海默病患者。2)在每个行为域中，我们将使用rna-seq来研究基因。 在每个BPSD结构域和基因所特有的不同脑亚区中的表达模式 将比较正常、MCI和AD受试者的表达模式。3)最后，我们将确定哪些 利用生物信息学和生物化学，通路与每一个bpsd结构域最清楚地联系在一起。 分析。对于动物模型的工作，1)我们将描述小鼠的行为如何类似于人类的BPSD 阿尔茨海默病样神经病变进展过程中的症状演变2)我们将确定最有希望的 使用这些AD/BPSD模型从我们的RNA-SEQ发现中进行干预的分子候选。3)最后，我们 将确定改变这些途径是否会导致使用病毒介导的BPSD样行为的改变 遗传操作(AAV9/CRISPR-CAS9)。总体而言，该项目将通过以下方式建立翻译管道 在人类AD患者中BPSD症状域与分子改变之间的关联，并通过展示 在AD转基因小鼠模型中，对这些通路的操纵可以导致类似BPSD的行为。 这些数据驱动的方法将使我们更好地理解其背后的分子机制 BPSD在AD中的作用，并有可能为未来的治疗干预确定新的靶点。