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

基本信息

批准号：
10183128
负责人：
Hongxin Dong
金额：
$ 69.25万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2018-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183128
关键词：
AD transgenic mice APP-PS1 Affect Affective Aggressive behavior Agitation Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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 Human Hyperactivity Impaired cognition Individual Institutionalization Intervention Investigation Lead Link Literature Mediating Memory Loss Memory impairment Mental Depression Methods Modeling Molecular 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

项目摘要

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.

概括超过90％的阿尔茨海默氏病（AD）患者患有行为和心理症状痴呆（BPSD），包括躁动，侵略，抑郁，冷漠和精神病。 BPSD可以出现在几乎所有AD的阶段，在某些患者中，这些症状甚至可以出现在痴呆症之前发展。随着疾病的发展，BPSD的严重程度显着增加，并影响生活质量在患者及其护理人员中。在许多患者中，BPSD是制度化的主要原因。但是，BPSD的基础机制尚不清楚，并且没有具体的治疗策略可用的。尽管BPSD在每个患者中的表现不同，但患者的某些症状存在使其他症状的同时出现更有可能。在与阿尔茨海默氏症的持续合作中疾病中心，我们开发了一种将BPSD症状聚集到四个领域的方法（情感，多动/抑制，精神病和冷漠）。基于这些域，我们进行了 RNA-seq并发现患有和不具有BPSD的AD患者中不同的基因表达谱。这个证据支持以下观点：BPSD的出现可能与不同的分子途径有关。在这个提案，我们假设AD患者的单个BPSD域是由于可定义的扰动引起的在分子途径中，可以在AD小鼠模型中类似这些途径，从而有因果关系研究特定途径改变与域行为之间的关系。我们将测试这个通过人类研究和动物工作的假设。对于人类研究，1）我们将扩展我们的行为分析通过增加受试者进行验尸临床评估并定义BPSD趋势随着时间的流逝，广告患者。 2）在每个行为领域，我们将采用RNA-Seq研究基因每个BPSD域和基因独有的不同大脑子区域中的表达模式将在正常，MCI和AD受试者之间进行比较。 3）最后，我们将确定哪个途径最明显地与每个BPSD域使用生物信息学和生化有关分析。对于动物模型的工作，1）我们将表征小鼠行为与人类BPSD类似的行为症状在类似AD的神经病变进展过程中演变2）我们将确定最有前途的使用这些AD/BPSD模型从我们的RNA-seq发现中进行干预的分子候选者。 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样行为发生变化遗传操作（AAV9/CRISPR-CAS9）。总体而言，该项目将通过将BPSD症状结构域与人类AD患者的分子改变相关联，并通过证明对这些途径的操纵可能会在AD的转基因小鼠模型中引起BPSD样行为。这些数据驱动的方法将使人们更好地了解基于的分子机制 BPSD在AD中，并有可能确定未来治疗干预措施的新靶标。