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Generation and characterization of a mouse model exhibiting beta-amyloidosis and tauopathy with nuclear depletion of TDP-43

具有 TDP-43 核耗竭的 β-淀粉样变性和 tau 蛋白病小鼠模型的生成和表征

基本信息

批准号：
10618759
负责人：
PHILIP C WONG
金额：
$ 66.7万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-17 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10618759
关键词：
APP-PS1 Address Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Amyloidosis Behavioral Biological Models Cognition Cognitive Cognitive deficits Defect Dementia Disease Disease Progression Educational Models Elderly Exhibits Exons Female Frontotemporal Dementia Generations Genes Human Knockout Mice Lewy Body Dementia Longevity Modeling Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Outcome Pathogenicity Pathologic Pathology Phase Phenotype Prosencephalon RNA Splicing Repression Role Senile Plaques Tauopathies Transgenes Validation age related aged cerebral atrophy cohort human disease innovation male meetings middle age mixed dementia mouse model neuron loss neuronal circuitry neurotoxicity novel protein TDP-43 scale up tau Proteins therapeutic target

项目摘要

Alzheimer's Disease-Related Dementias (ADRD) is a group of progressive neurodegenerative disorders with mid to late life onset such as mixed etiology dementias (MED) including Alzheimer's disease (AD) with TDP-43 pathology. To clarify disease mechanisms and identify therapeutic targets, a new mouse models that replicate combinations of co-occurring pathological features of human dementia will be critical. It is well recognized that AD cases with TDP-43 pathology, as compared to those without, showed a greater decline in cognitive deficits. However, the molecular mechanisms underlying such contribution of TDP-43 remains elusive. We showed that TDP-43 pathology is due to loss of TDP-43's nuclear function, particularly its ability to repress cryptic exon splicing, that precedes formation of TDP-43 cytoplasmic aggregates. That splicing repression is a major role of TDP-43 in forebrain neurons led us to hypothesize that loss of TDP-43 repression exacerbates neurodegeneration and cognitive deficits. To address this question, we will take advantage of 1) our model lacking TDP- 43 in forebrain neurons which exhibits age-dependent neuron loss, cognitive deficits and defects in prelimbic cortical circuits; and 2) our tau model which show, in presence of amyloid plaques, tauopathy- dependent neuron loss, to develop a novel MED model that would exhibit beta-amyloidosis and tauopathy along with compromised TDP-43 repression in forebrain neurons, pathological features that mimic AD with loss of TDP-43 repression. By employing a comprehensive set of molecular, pathological, neuronal circuit and behavioural/cognitive approaches, we will rigorously characterize the MED mice across their lifespan, providing a highly innovative and instructive model to clarify disease mechanism and identify therapeutic targets.

阿尔茨海默病相关痴呆(ADRD)是一组进行性神经退行性变中老年起病的疾病，如混合病因痴呆(MED)，包括阿尔茨海默氏症疾病(AD)与TDP-43病理。为了阐明疾病机制并确定治疗靶点，一种复制人类共生病理特征组合的新小鼠模型痴呆症将是至关重要的。众所周知，与TDP-43病理的AD病例相比，而那些没有这样做的人，在认知缺陷方面的下降幅度更大。然而，分子机制 TDP-43的潜在贡献仍然难以捉摸。我们发现TDP-43的病理是由于 Tdp-43‘S核功能的丧失，特别是其抑制隐蔽外显子剪接的能力 TDP-43胞质聚集体的形成。剪接抑制是TDP-43在前脑神经元导致我们假设失去TDP-43抑制会加剧神经退行性变和认知缺陷。为了解决这个问题，我们将利用1)我们的模型缺乏TDP- 43在前脑神经元中表现出年龄依赖性神经元丢失，认知障碍和脑功能缺陷 2)我们的tau模型显示，在存在淀粉样斑块的情况下，tau病- 依赖性神经元丢失，以建立一种新的MED模型，该模型将显示β淀粉样变性和伴随着TDP-43抑制受损的前脑神经元的TDP-43的病理特征模拟AD，失去TDP-43抑制。通过使用一套全面的分子，病理、神经回路和行为/认知方法，我们将严格描述 MED小鼠的整个生命周期，提供了一种高度创新和具有启发性的模型来澄清疾病作用机制和确定治疗靶点。