Auditory neuronal degeneration in an ahl-corrected mouse model of Alzheimer's disease

摘要 阿尔茨海默病（AD）是年龄相关性痴呆的最常见原因。AD的病理变化 在老年斑（SP）和微管相关性斑块中，β淀粉样蛋白（Aβ）是一种明确的特征性蛋白。 神经元缠结（NFT）中的tau蛋白（MAPT）。A β前体蛋白（APP）突变与早期- 发病家族性AD，建立了老年斑病理学的发展和AD之间的联系。然而，在这方面， 目前还没有AD的治疗或预防策略，这主要是由于缺乏有效的治疗方法。 全面了解早期检测的精确分子机制。 我们将在一种新的动物模型中将我们的研究扩展到早发性家族性AD（FAD）。 补充建议。来自病例对照和纵向人群研究的证据已经确立 年龄相关性听力损失（ARHL）与认知障碍和痴呆症之间存在很强的相关性。没有 有证据表明AD和听觉缺陷之间存在特定联系，尤其是机械联系。在 与Sambamurti博士合作，我们最近开发了一种表达FAD的Ahl校正的FAD小鼠模型， APP和PSEN 1的突变，称为FADc/c小鼠。这种策略消除了已知的遗传阿勒 加速年龄相关性听力损失（ARHL）突变，揭示AD病理介导的听力障碍。我们 初步结果显示，C57 BL/6 J品系背景的雌性和雄性FADc/c小鼠均具有 在9-10个月龄时，在8、16和32 kHz下测量的听阈显著高于 野生型（WTc/c）小鼠，几乎90%的雌性和40%的雄性显示阈值严重升高 高于60 dB SPL。我们的初步研究结果还表明，海马淀粉样蛋白沉积的程度， FADc/c小鼠在9-10月龄时评估时与听力损失的严重程度相关。基于我们 初步的实验数据和文献表明淀粉样病变可诱导听觉损伤， 在动物模型中，我们将测试我们的假设，即由FAD突变触发的神经退行性通路， 促进听觉神经功能障碍。这一假设的延伸是将听力损失作为一种功能性评估， 在那些有易感性的人中，AD的生物标志物。此外，最近的一项研究表明，适度的噪音 暴露加速了三重转基因小鼠模型的认知能力下降。因此，我们将进一步测试， 环境对听觉系统的损害，如噪音引起的隐性听力损失， 通过压力和AD介导的炎症的组合，降低AD易感性。 总之，我们的建议将评估APP和PS1中的FAD突变对听力损失的影响， Ahl校正的转基因小鼠。此外，我们将评估环境因素，如温和的 噪音暴露，在小鼠与AD易感性加速认知能力下降。这些结果可能会提供一些见解， 一个允许干预的时间框架。

Abstract Alzheimer's disease (AD) is the most common cause of age-related dementia. The pathological changes of AD are well defined and characterized by amyloid β protein (Aβ) in senile plaques (SP) and microtubule-associated protein tau (MAPT) in neurofibrillary tangles (NFTs). A precursor protein (APP) mutations are linked to early- onset familial AD, establishing a link between development of senile plaque pathology and AD. However, currently there are no treatments or preventative strategies for AD available, owed largely to the lack of a comprehensive understanding of the precise molecular mechanisms for earlier detection. We will extend our investigation to early-onset familial AD (FAD) in a novel animal model for this supplement proposal. Evidence from case-controlled and longitudinal population-based studies has established a strong correlation between age-related hearing loss (ARHL) and cognitive impairment and dementia. No evidence exists showing a specific link between AD and auditory deficits, especially a mechanistic link. In collaboration with Dr. Sambamurti, we recently developed an Ahl-corrected FAD mouse model expressing FAD mutations of APP and PSEN1, referred to as FADc/c mice. This strategy eliminated the known genetic Ahl accelerated age-related hearing loss (ARHL) mutation, uncovering AD-pathology-mediated hearing deficits. Our preliminary results show that both female and male FADc/c mice on a C57BL/6J strain background have significantly higher auditory thresholds measured at 8, 16, and 32 kHz at the age of 9–10 months compared to wild-type (WTc/c) mice with almost 90% of females and 40% of males showing severely elevated thresholds above 60 dB SPL. Our preliminary results also show that the extent of amyloid deposition in the hippocampus of FADc/c mice correlates with the severity of hearing loss when assessed at the age of 9–10 months. Based on our preliminary experimental data and literature suggesting that amyloid pathology can induce auditory impairment in animal models, we will test our hypothesis that neurodegenerative pathways triggered by FAD mutations promote auditory nerve dysfunction. An extension of this hypothesis is to evaluate hearing loss as a functional biomarker for AD in those with a predisposition. Additionally, one recent study indicated that moderate noise exposure accelerates cognitive decline in a triple transgenic mouse model. Thus we will further test whether environmental insults to the auditory system, such as noise-induced hidden hearing loss, may hasten cognitive decline in those with predisposition to AD via a combination of stress and AD-mediated inflammation. In summary, our proposal will assess the effects of FAD mutations in APP and PS1 on hearing loss in Ahl-corrected transgenic mice. Furthermore, we will assess whether environmental factors, such as moderate noise exposure, in mice with predisposition for AD accelerate cognitive decline. The results may provide insight into a timeframe that would allow for intervention.