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% 的阿尔茨海默病 (AD) 患者患有以下行为和心理症状痴呆症（BPSD）包括激越、攻击性、抑郁、冷漠和精神病。 BPSD 可以出席几乎 AD 的任何阶段，在某些患者中，这些症状甚至可以在痴呆之前出现发展。 BPSD 的严重程度随着疾病进展而显着增加，并影响生活质量患者及其护理人员。在许多患者中，BPSD 是住院的主要原因。然而，BPSD的机制尚不清楚，也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，但患者中存在某些症状使其他症状同时出现的可能性更大。与 Rush 阿尔茨海默氏症持续合作疾病中心，我们开发了一种将 BPSD 症状聚类为四个领域的方法（情感、多动/抑制解除、精神病和冷漠）。基于这些领域，我们随后进行了 RNA-seq 发现患有和不患有 BPSD 的 AD 患者存在不同的基因表达谱。这个证据支持这样的观点：不同的分子途径可能与 BPSD 的出现有关。在这个提议，我们假设 AD 患者的个体 BPSD 域是由于可定义的扰动造成的这些途径可以在 AD 小鼠模型中进行类比，从而可以得出因果关系研究特定通路改变和域行为之间的关系。我们将测试这个通过人类研究和动物研究得出的假设。对于人类研究，1）我们将扩展我们的通过增加死前临床评估对象和定义 BPSD 趋势进行行为分析随着时间的推移，AD 患者。 2）在每个行为领域，我们将采用RNA-seq来研究基因每个 BPSD 结构域和基因在不同大脑亚区域中的表达模式是独特的将比较正常、MCI 和 AD 受试者的表达模式。 3）最后，我们将确定哪些使用生物信息学和生物化学，途径与每个 BPSD 域的关联最为清晰分析。对于动物模型工作，1）我们将描述小鼠行为与人类 BPSD 的相似之处症状在 AD 样神经病变进展过程中演变 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 结果中得出干预的分子候选者。 3）最后，我们将使用病毒介导的方法确定改变这些途径是否会导致 BPSD 样行为的变化基因操作（AAV9/CRISPR-Cas9）。总体而言，该项目将建立一个翻译管道将 BPSD 症状域与人类 AD 患者的分子改变联系起来，并通过证明操纵这些通路可以在 AD 转基因小鼠模型中引起类似 BPSD 的行为。这些数据驱动的方法将有助于更好地理解其背后的分子机制 AD 中的 BPSD 并可能确定未来治疗干预的新靶标。