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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos 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&apos 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

项目摘要

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.

抽象的阿尔茨海默病（AD）是年龄相关性痴呆的最常见原因 AD 的病理变化。老年斑 (SP) 中的淀粉样蛋白 (Aβ) 和微管相关蛋白具有明确的定义和特征神经原纤维缠结 (NFT) 中的 tau 蛋白 (MAPT) 突变与早期相关。家族性 AD 发病，建立了老年斑病理学与 AD 之间的联系。目前尚无 AD 可用的治疗或预防策略，这主要是由于缺乏有效的方法。全面了解早期检测的精确分子机制。为此，我们将在一种新型动物模型中将我们的研究扩展到早发家族性 AD (FAD) 补充提案的证据来自病例对照和纵向人群研究。年龄相关性听力损失 (ARHL) 与认知障碍和痴呆之间存在很强的相关性。现有证据表明 AD 和听觉缺陷之间存在特定联系，尤其是机械联系。我们与 Sambamurti 博士合作，最近开发了表达 FAD 的 Ahl 校正 FAD 小鼠模型 APP 和 PSEN1 突变，称为 FADc/c 小鼠，该策略消除了已知的基因 Ahl。加速年龄相关性听力损失（ARHL）突变，揭示 AD 病理介导的听力缺陷。初步结果表明，C57BL/6J 品系背景下的雌性和雄性 FADc/c 小鼠均具有与 9-10 个月大的婴儿相比，在 8、16 和 32 kHz 下测得的听觉阈值明显更高野生型 (WTc/c) 小鼠中，几乎 90% 的雌性小鼠和 40% 的雄性小鼠表现出严重升高的阈值我们的初步结果还表明，当声压级高于 60 dB 时，海马中淀粉样蛋白沉积的程度会增加。根据我们的研究，在 9-10 个月时进行评估时，FADc/c 小鼠与听力损失的严重程度相关。初步实验数据和文献表明淀粉样蛋白病理可诱发听觉障碍在动物模型中，我们将检验我们的假设，即 FAD 突变引发的神经退行性通路该假设的延伸是将听力损失作为一种功能性评估。此外，最近的一项研究表明，中度噪音是有 AD 倾向的人的生物标志物。暴露会加速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是否如此。环境对听觉系统的损害，例如噪音引起的隐性听力损失，可能会加速认知能力的下降由于压力和 AD 介导的炎症的结合，AD 易感人群的患病率下降。总之，我们的提案将评估 APP 和 PS1 中的 FAD 突变对听力损失的影响此外，我们将评估环境因素，例如适度的环境因素。患有 AD 倾向的小鼠的噪音暴露会加速认知能力下降。进入一个允许干预的时间范围。