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

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。

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.