Selective over expression of TDP-43 in APP/PS1 mice alters APP processing

描述（由申请人提供）：阿尔茨海默病（AD）的最大危险因素是老龄化，估计有530万65岁及以上的人患有该疾病。阿尔茨海默病的病理主要包括淀粉样斑块和由微管相关蛋白tau组成的神经原纤维缠结（NFT）。额颞叶痴呆和运动神经元疾病的主要病理蛋白是43 kDa的交互反应dna结合蛋白（TDP-43）。与tau类似，病理性的TDP-43会过度磷酸化，并存在于神经元包涵体中。最近，在高达50%的散发性阿尔茨海默病病例和14%的家族性阿尔茨海默病病例中也发现了TDP-43聚集。我们描述了在皮质神经元培养中，TDP-43的过表达会增加b-分泌酶（Bace1）蛋白水平，而TDP-43的敲低会改变b和g c端片段的加工。此外，在皮质和海马神经元选择性过表达TDP-43的APP/PS1小鼠中，淀粉样蛋白沉积的明显变化与过表达Bace1的APP小鼠相似。基于这些观察结果，我们假设TDP-43表达的变化改变了APP/PS1小鼠的APP加工和Bace1活性。这种神经元和/或胶质特异性人类TDP-43的过度表达将导致APP加工的改变、行为缺陷和随后的神经退行性变。在阿尔茨海默病小鼠模型中，TDP-43表达影响Bace1活性的相关机制尚未被探索。在这个体内小鼠模型中，我们想要探索TDP-43的细胞特异性表达对阿尔茨海默病的神经发病机制有什么影响。对于那些患有阿尔茨海默病的人来说，BACE活性的增加与年龄有关，增加了APP处理，导致神经变性加速。了解与这些变化相关的机制以及年龄如何起作用可以丰富我们对阿尔茨海默病进展的理解。这种体内模型可能会导致针对减缓进展的新疗法的发展。

DESCRIPTION (provided by applicant): The greatest risk factor for Alzheimer's disease (AD) is aging, with an estimated 5.3 million people aged 65 and older with the disease. The pathology of AD consists primarily of amyloid-beta plaques and neurofibrillary tangles (NFT) composed of microtubule-associated protein tau. The major pathological protein in frontotemporal dementia and motor neuron disease is Transactive response DNA-binding Protein of 43 kDa (TDP-43). Similar to tau, pathological TDP-43 becomes hyper-phosphorylated and is present in neuronal inclusions. Recently, TDP-43 aggregation has also been described in up to 50% of sporadic and 14% of familial Alzheimer's disease cases. We describe that overexpression of TDP-43 increases b-secretase (Bace1) protein levels and knockdown of TDP-43 alters b and g C-terminal fragment processing in cortical neuron cultures. Also, in APP/PS1 mice selectively over-expressing TDP-43 in cortical and hippocampal neurons there is a distinct change in amyloid deposition similar to what is observed in APP mice over-expressing Bace1. Based on these observations, we hypothesize that changes in TDP-43 expression alters APP processing and Bace1 activity in APP/PS1 mice. This overexpression of neuronal and/or glial specific human TDP-43 will lead to changes in APP processing, behavioral deficits, and subsequent neurodegeneration. Mechanisms associated with TDP-43 expression affecting Bace1 activity in an Alzheimer's disease mouse model have not been explored. In this in vivo mouse model we want to explore what effect cell-specific expression of TDP-43 has on the neuropathogenesis of Alzheimer's disease. For those suffering from Alzheimer's disease there is an age-dependent increase BACE activity increasing APP processing leading to accelerated neurodegeneration. Understanding mechanisms associated with these changes and how age contributes could enrich our understanding of the progression of Alzheimer's disease. This in vivo model potentially could lead to the development of new therapeutics targeted at slowing the progression.