Examination of the bidirectional relationship between hearing loss and Alzheimer Disease pathology

听力损失与阿尔茨海默病病理学之间双向关系的检查

• 批准号: 10356939
• 负责人: DANIEL A LLANO
• 金额: $ 24.16万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356939
• 关键词: APP-PS1; Acceleration; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Apolipoprotein E; Auditory; Auditory Brainstem Responses; Auditory Threshold; Auditory system; Behavioral; Brain; Cardiovascular Diseases; Cell Cycle; Central Auditory Diseases; Characteristics; Clinical; Cochlear Implants; Data; Dementia; Deposition; Development; Dichotic Listening Tests; Disease; Early Diagnosis; Early Intervention; Etiology; Exposure to; Future; Genes; Genetic Predisposition to Disease; Genotype; Hearing; Hearing Aids; Hearing problem; High Prevalence; Hippocampus (Brain); Image; Impairment; Individual; Intervention; Large T Antigen; Learning; Link; Measures; Modeling; Molecular; Mus; Mutation; Nature; Nerve Degeneration; Neurofibrillary Tangles; Noise; Noise-Induced Hearing Loss; Pathology; Pathway interactions; Peripheral; Phenotype; Population; Positron-Emission Tomography; Presbycusis; Prevalence; Process; Public Health; Quality of life; Research; Research Personnel; Research Proposals; Risk; Risk Factors; Rodent; Specimen; Testing; Time; Training; Work; abeta deposition; aging population; auditory processing; aural rehabilitation; base; behavior test; cognitive change; drug development; effective therapy; epidemiology study; familial Alzheimer disease; fluorodeoxyglucose positron emission tomography; hearing impairment; human old age (65+); human subject; improved; morris water maze; mouse model; neurodegenerative phenotype; new therapeutic target; noise exposure; novel; otoacoustic emission; response; simian virus; speech in noise; successful intervention; tau Proteins; tau-1; treatment strategy

ABSTRACT Recent epidemiological studies have revealed an association between aging-related hearing loss (ARHL) and Alzheimer Disease (AD). Both of these disorders deprive individuals of their quality of life and both are rapidly rising in prevalence, given the aging of our population. Therefore, it is critical that we understand how AD and ARHL are related and whether this relationship can be used as leverage to better understand and treat both disorders. One key question is whether ARHL and AD are linked because of common risk factors or whether there is a causal relationship between the two (i.e., does ARHL exacerbate AD pathology?). This question cannot be answered effectively in human subjects because of the inability to independently manipulate hearing loss. Therefore, in the current study, we employ two animal models of AD (a model of sporadic and a model of familial AD) and ask whether manipulation of the peripheral auditory system alters AD pathology. To do this, we employ a novel model of sporadic AD that is based on cell-cycle dysregulation – a phenomenon that is commonly observed in brain specimens from AD patients. These AD model mice therefore do not carry a specific mutation in a gene that directly processes amyloid beta or tau. Nevertheless, they have been shown to display characteristic plaques and tangles, similar to what is seen in the AD brain, and neurodegeneration, which is not seen in most other mouse models of sporadic AD. The model of familial AD that will be used is the APP/PS1 mouse because it has been shown to display central auditory dysfunction and has a time course of pathology that matches with our sporadic AD model. In Aim 1, we will test both peripheral and central auditory function in these mice and hypothesize that, like AD patients, they will have more impairment in central, compared to peripheral, auditory function. In Aim 2, we will induce hearing loss and examine for exacerbation of AD pathology and induction of a progressive neurodegenerative phenotype using a combination of serial FDG PET imaging and behavioral analyses. We hypothesize that hearing loss will worsen AD pathology and exploratory analyses will be done to determine if changes are more severe in central auditory compared to non-auditory regions. Successful completion of this work will, for the first time, determine the nature of the association between hearing loss and AD pathology. If a causal association is found, future work will determine the molecular mechanisms of this association and whether mitigation of ARHL also diminishes AD pathology. Given the advancing pace of successful interventions for ARHL (aural rehabilitation, “smart” hearing aids, cochlear implants, etc.), this research could lay the groundwork for early intervention for ARHL to diminish the burden of dementia.

抽象的 最近的流行病学研究表明，与衰老相关的听力损失之间存在关联 （ARHL）和阿尔茨海默氏病（AD）。这两种疾病都剥夺了个人的质量 鉴于我们人口的老化，生命和两者的流行速度正在迅速上升。因此，是 我们了解AD和ARHL的关系以及这种关系是否可以是至关重要的 用作更好地理解和治疗这两种疾病的杠杆。一个关键问题是是否 ARHL和AD由于共同的风险因素而被联系起来，或者是否存在因果关系 在两者之间（即ARHL会加剧AD病理学？）。这个问题无法回答 由于无法独立操纵听力损失，因此有效地在人类受试者中。 因此，在当前的研究中，我们采用了两种AD动物模型（一种零星和A模型 家庭广告模型），询问操纵外围听觉系统是否改变了广告 病理。为此，我们采用了基于细胞周期的新型零星AD模型 失调 - AD患者的脑标本中通常观察到的一种现象。 因此，这些AD模型小鼠不会在直接处理的基因中携带特定突变 淀粉样β或tau。尽管如此，它们已被证明显示出特征性的斑块和 缠结，类似于广告大脑中看到的缠结和神经变性，大多数人都看不到 其他零星AD的小鼠模型。将使用的家庭广告模型是应用程序/PS1 鼠标因为已显示出显示中央听觉功能障碍并具有时间课程 与我们零星的广告模型相匹配的病理学。在AIM 1中，我们将测试外围和 这些小鼠中的中央听觉功能，并假设像AD患者一样，他们将拥有更多 与外围，听觉功能相比，中央损伤。在AIM 2中，我们将诱使听力 加剧AD病理学和诱导性的损失和检查 神经退行性表型，结合了串行FDG PET成像和行为的组合 分析。我们假设听力损失将导致AD病理和探索性分析 与非审计相比，将完成中央听觉的更改是否更严重 地区。成功完成这项工作将首次确定 听力损失与AD病理学之间的关联。如果发现因果关系，未来的工作 将确定这种关联的分子机制以及是否也缓解ARHL 减少AD病理学。鉴于ARHL成功干预的进步速度（听觉 康复，“智能”助听器，人工耳蜗等），这项研究可能会构成 早期干预的基础，以减少痴呆症的燃烧。