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.

抽象的 最近的流行病学研究揭示了与衰老相关的听力损失之间的关联 （ARHL）和阿尔茨海默病（AD）这两种疾病都会剥夺个体的素质。 鉴于我们人口的老龄化，两者的患病率都在迅速上升。 至关重要的是我们了解 AD 和 ARHL 之间的关系以及这种关系是否可以 一个关键问题是是否可以作为更好地理解和治疗这两种疾病的杠杆。 ARHL 和 AD 因共同危险因素或是否存在因果关系而存在关联 两者之间（即 ARHL 是否会使 AD 病理恶化？这个问题无法回答）。 由于无法独立控制听力损失，因此在人类受试者中有效。 因此，在当前的研究中，我们采用了两种 AD 动物模型（散发性模型和 家族性 AD 模型）并询问外周听觉系统的操纵是否会改变 AD 为此，我们采用了一种基于细胞周期的新型散发性 AD 模型。 失调——这种现象在 AD 患者的大脑标本中常见。 因此，这些 AD 模型小鼠的直接处理基因不携带特定突变。 然而，β 淀粉样蛋白或 tau 淀粉样蛋白已被证明表现出特征性斑块和 缠结，类似于 AD 大脑中所见的情况，以及神经变性，这在大多数情况下都不会出现 散发性 AD 的其他小鼠模型 将使用的家族性 AD 模型是 APP/PS1。 小鼠，因为它已被证明表现出中枢听觉功能障碍并且具有时间过程 在目标 1 中，我们将测试外周和 AD 模型的病理学。 这些小鼠的中枢听觉功能，就像 AD 患者一样，它们会有更多 与外周听觉功能相比，中枢听觉功能受损 在目标 2 中，我们将诱发听力。 损失和检查 AD 病理学检查和进展的诱导 使用连续 FDG PET 成像和行为学相结合的神经退行性表型 我们追求听力损失会恶化 AD 病理学和探索性分析。 将确定中枢听觉的变化是否比非听觉的变化更严重 这项工作的成功完成将首次决定该地区的性质。 听力损失与 AD 病理之间的关联 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 ARHL 的缓解是否也有效 鉴于 ARHL（听觉）干预措施的成功进展，减少了 AD 病理学。 康复、“智能”助听器、人工耳蜗等），这项研究可以奠定 为 ARHL 早期干预以减轻痴呆症负担奠定基础。