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

摘要 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联系 (ARHL)和阿尔茨海默病(AD)。这两种疾病都剥夺了个体的素质 鉴于我们人口的老龄化，这两种疾病的患病率都在迅速上升。因此，它是 我们必须了解AD和ARHL是如何相关的，以及这种关系是否可以 被用作更好地理解和治疗这两种疾病的筹码。一个关键的问题是 ARHL和AD是因为共同的风险因素或是否存在因果关系而联系在一起的 两者之间的关系(即，ARHL是否加剧了AD的病理？)这个问题无法回答 由于无法独立处理听力损失，因此在人类受试者中有效。 因此，在本研究中，我们采用了两种AD动物模型(散发性AD模型和 家族性阿尔茨海默病模型)，并询问周围听觉系统的操作是否改变了阿尔茨海默病 病理学。为了做到这一点，我们采用了一种基于细胞周期的散发性AD模型 调节失调--这是一种在AD患者的大脑样本中常见的现象。 因此，这些阿尔茨海默病模型小鼠不携带直接处理 淀粉样β蛋白或tau蛋白。尽管如此，它们已被证明显示出特有的斑块和 缠结，类似于在AD大脑中看到的，以及神经退化，这在大多数情况下都不存在 其他散发性AD小鼠模型。将使用的家族性AD的模型是APP/PS1 小鼠，因为它已经被证明表现出中枢听觉功能障碍，并有一个时间过程 与我们的散发性阿尔茨海默病模型相符的病理特征。在目标1中，我们将测试外围设备和 这些小鼠的中枢听觉功能，并假设，像AD患者一样，他们会有更多 与外周听觉功能相比，中枢受损。在目标2中，我们将诱导听力 阿尔茨海默病病理加重及诱发进展性病变的丢失和检查 系列FDG PET成像与行为学相结合的神经退行性变表型 分析。我们假设听力损失将加重AD的病理和探索性分析 以确定中枢听觉的改变是否比非听觉的改变更严重 地区。这项工作的成功完成将第一次决定 听力损失与AD病理的关系。如果发现了因果关系，则未来的工作 将确定这种联系的分子机制，以及ARHL的缓解是否也 减少AD的病理改变。鉴于ARHL(听觉)成功干预的进展速度 康复、智能助听器、人工耳蜗等)，这项研究可以为 为ARHL的早期干预奠定基础，以减轻痴呆的负担。

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.