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: 10196576
• 负责人: DANIEL A LLANO
• 金额: $ 20.19万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196576
• 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; 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.

摘要 最近的流行病学研究揭示了与年龄相关的听力损失 （ARHL）和阿尔茨海默病（AD）。这两种疾病都剥夺了个体的品质 随着人口老龄化，这两种疾病的流行率都在迅速上升。因此有 关键是我们要了解AD和ARHL是如何相关的，以及这种关系是否可以 作为杠杆来更好地理解和治疗这两种疾病。一个关键问题是， ARHL和AD由于共同的风险因素或是否存在因果关系而相关 两者之间（即，ARHL是否会加重AD病理学？）。这个问题无法回答 由于不能独立地控制听力损失，因此在人类受试者中有效。 因此，在目前的研究中，我们采用了两种AD动物模型（散发性模型和非散发性模型）。 家族性AD模型），并询问外周听觉系统的操作是否会改变AD 病理为此，我们采用了一种基于细胞周期的散发性AD新模型， 调节异常-这是在AD患者的脑样本中常见的现象。 因此，这些AD模型小鼠不携带直接处理AD的基因中的特定突变。 淀粉样蛋白β或tau。尽管如此，它们已被证明显示出特征性斑块， 缠结，类似于在AD大脑中看到的，以及神经变性，这在大多数人中都没有看到。 其他散发性AD的小鼠模型。将使用的家族性AD模型是APP/PS1 小鼠，因为它已被证明显示中枢听觉功能障碍， 符合我们的偶发性AD模型在目标1中，我们将测试外围设备和 他们假设，像AD患者一样，他们将有更多的听觉中枢功能， 与周边听觉功能相比，中枢听觉功能受损。在目标2中，我们将诱导听力 损失和检查AD病理恶化和诱导进行性 使用连续FDG PET成像和行为学相结合的神经退行性表型 分析。我们假设听力损失会使AD病理恶化， 以确定与非听觉相比，中枢听觉的变化是否更严重 地区这项工作的成功完成将首次确定 听力损失与AD病理学之间的联系。如果发现了因果关系， 将确定这种关联的分子机制，以及缓解ARHL是否也 减少AD病理学。鉴于ARHL成功干预的进展速度（耳 康复、“智能”助听器、人工耳蜗等），这项研究可以奠定 为ARHL的早期干预奠定基础，以减轻痴呆的负担。