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）的最大风险因素是衰老，估计有530万65岁及以上的人患有这种疾病。AD的病理学主要由β淀粉样蛋白斑块和由微管相关蛋白tau组成的神经元缠结（NFT）组成。额颞叶痴呆和运动神经元病的主要病理蛋白是43 kDa的反式反应DNA结合蛋白（TDP-43）。与tau类似，病理性TDP-43变得过度磷酸化并存在于神经元包涵体中。最近，TDP-43聚集也被描述在高达50%的散发性和14%的家族性阿尔茨海默病病例中。我们描述了TDP-43的过表达增加了b-分泌酶（Bace 1）蛋白水平，而TDP-43的敲低改变了皮层神经元培养物中B和g C-末端片段的加工。此外，在APP/PS1小鼠选择性过度表达TDP-43的皮质和海马神经元中，淀粉样蛋白沉积有明显的变化，类似于APP小鼠过度表达Bace 1。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Bace 1活性。神经元和/或神经胶质特异性人TDP-43的这种过表达将导致APP加工、行为缺陷和随后的神经变性的变化。在阿尔茨海默病小鼠模型中，TDP-43表达影响Bace 1活性的相关机制尚未研究。在这个体内小鼠模型中，我们想探索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活性随着年龄的增长而增加，增加APP加工，导致神经退行性变加速。了解与这些变化相关的机制以及年龄的贡献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开发新的治疗方法，以减缓进展。

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.