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

描述(申请人提供)：阿尔茨海默病(AD)的最大风险因素是老龄化，估计有530万65岁及以上的人患有这种疾病。AD的病理主要由淀粉样β斑块和微管相关蛋白tau组成的神经原纤维缠结(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过度磷酸化，并存在于神经元包涵体中。最近，多达50%的散发性和14%的家族性阿尔茨海默病病例中也描述了TDP-43聚集。与磷酸化TDP-43病理堆积相关的机制，以及它与淀粉样蛋白沉积、NFT形成和神经元变性等AD病理之间的关系尚未被探索。随着内源性磷酸化TDP-43在APP/PS1小鼠的海马区和皮质中的积累，我们假设TDP-43的过度表达将改变TDP-43和/或Aβ沉积的病理年龄相关性变化。对于那些患有阿尔茨海默病的人来说，病情恶化是不可避免的。Abeta沉积的增加导致TDP-43的溶解性、定位和磷酸化随年龄变化。了解与这些变化相关的机制以及年龄如何导致TDP-43积累增加，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以减缓进展为目标的新疗法的开发。

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. Mechanisms associated with accumulation of phosphorylated TDP-43 pathology and how it relates to AD pathology with respect to amyloid deposition, NFT formation, and neuronal degeneration have not been explored. With an accumulation of endogenous phosphorylated TDP-43 in the hippocampus and cortex of APP/PS1 mice, we hypothesize that TDP-43 overexpression will alter pathological age-dependent changes in TDP-43 and/or Abeta deposition. For those suffering from Alzheimer's disease, progression is inevitable. Increases in Abeta deposition cause an age-dependent change in solubility, localization, and phosphorylation of TDP-43. Understanding mechanisms associated with these changes and how age contributes to increased accumulation of TDP-43 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.