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

ahl 校正的阿尔茨海默病小鼠模型中的听觉神经元变性

• 批准号: 10711404
• 负责人: Su-Hua Sha
• 金额: $ 33.83万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711404
• 关键词: 3xTg-AD mouse; Acceleration; Acoustic Nerve; Administrative Supplement; Age; Age Months; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Animal Model; Auditory; Auditory Threshold; Auditory system; Biological Markers; CBA/J Mouse; CDH23 gene; Cognitive; Collaborations; Data; Dementia; Deposition; Development; Ear; Early Diagnosis; Early Onset Familial Alzheimer' s Disease; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Evaluation; Exposure to; Feedback; Female; Frequencies; Functional disorder; Future; Gender; Genes; Genetic; Golgi Apparatus; Hair Cells; Hippocampus; Hybrids; Impaired cognition; Impairment; Inbreeding; Inflammation; Inner Hair Cells; Intervention; Investigation; Left; Left cerebral hemisphere; Link; Literature; MAPT gene; Measures; Mediating; Methods; Modeling; Molecular; Mus; Mutation; Myelin Sheath; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Noise; Pathologic; Pathology; Pathway interactions; Population Study; Predisposition; Preparation; Presbycusis; Prevention strategy; Protein Precursors; Reporting; Research; Right cerebral hemisphere; Senile Plaques; Sensory Hair; Severities; Stains; Stress; Structure; Surface; Synapses; TNF gene; Testing; Tissues; Transgenic Mice; Transgenic Model; Vertebral column; Western Blotting; Wild Type Mouse; age related; amyloid pathology; auditory deprivation; behavior test; brain tissue; case control; cerebral atrophy; density; familial Alzheimer disease; ganglion cell; hearing impairment; hidden hearing loss; improved; insight; male; mouse model; mutant; mutation correction; myelin degeneration; neuron loss; noise exposure; novel; postsynaptic density protein; premature; presenilin-1; presenilin-2; preservation; prevent hearing loss; progression marker; ribbon synapse; spiral ganglion; treatment strategy

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.

抽象的 阿尔茨海默氏病（AD）是与年龄有关的痴呆症的最常见原因。广告的病理变化 在老年斑（SP）和微管相关的淀粉样β蛋白（Aβ）和相关的淀粉样β蛋白（Aβ）中得到很好的定义和特征 神经原纤维缠结（NFTS）中的蛋白质tau（mapt）。 A前体蛋白（APP）突变与早期有关 发作家庭广告，建立老年斑块病理学发展与AD之间的联系。然而， 目前尚无治疗或预防策略可用的广告，主要是由于缺乏 对早期检测的精确分子机制的全面理解。 我们将在新型动物模型中将投资扩展到早期发作的家族广告（FAD） 补充建议。来自病例控制和基于纵向人群的研究的证据已建立 与年龄相关的听力损失（ARHL）与认知障碍和痴呆症之间的密切相关。不 存在证据，显示AD和听觉之间的特定联系定义，尤其是机械链接。在 与Sambamurti博士的合作，我们最近开发了一种经AHL校正的FAD鼠标模型，表达了FAD APP和PSEN1的突变，称为FADC/C小鼠。该策略消除了已知的遗传AHL 加速与年龄相关的听力损失（ARHL）突变，发现AD-PARTOROGY介导的听力缺陷。我们的 初步结果表明，C57BL/6J菌株背景上的雌性和雄性FADC/C小鼠均具有 与9-10个月的8、16和32 kHz测得的听觉阈值明显更高 野生型（WTC/C）小鼠，近90％的女性和40％的男性显示出严重升高的阈值 高于60 dB的Spl。我们的初步结果还表明，海马中淀粉样蛋白沉积的程度 FADC/C小鼠在9-10个月大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理可以诱导听觉障碍 在动物模型中，我们将测试我们的假设，即神经退行性途径是由FAD突变触发的 促进听觉神经功能障碍。该假设的扩展是评估听力损失作为功能 具有易感性的人的AD生物标志物。此外，最近的一项研究表明现代噪音 暴露在三重转基因小鼠模型中加速了认知能力下降。我们将进一步测试是否 对听觉系统的环境侮辱，例如噪声引起的隐藏听力损失，可能会出现认知 通过压力和AD介导的炎症的结合，患有AD的人的下降。 总而言之，我们的建议将评估APP和PS1中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（例如现代）是否 噪声暴露，在易感性认知能力下降的小鼠中。结果可能会提供洞察力 进入允许干预的时间表。