In VIvo Proteolysis and Axonal Transport in Tauopathy

神经元体细胞树突间内tau的异常积聚 阿尔茨海默病(AD)和其他神经病变是一种标志性的神经病理损害，与神经退行性变的机制尚不清楚。病理性tau的积聚很可能在很大程度上与tau翻译后的命运有关，但人们对tau在正常神经元或神经病理状态下的周转或轴突运输知之甚少。此外，tau积聚的不良后果很可能包括导致神经变性的继发性转运障碍和蛋白水解酶的激活。这项建议的总体目标是通过系统分析野生型tau在神经元中过度表达对轴突运输和可能代谢tau的主要蛋白分解系统的影响，提供有关tau翻译后行为的基本信息。这些研究将专门测试以下假设：与年龄相关的tau蛋白分解或轴突运输的改变有助于tau的积累，以及对tau积累/功能障碍的异常蛋白分解反应促进神经退化。为了实现这些目标，我们建议：1)评估包括tau转运在内的慢转运和快转运机制在野生型小鼠和tau相关神经变性小鼠模型中的能力；tau相关神经变性表现为与年龄相关的tau蓄积和细胞丢失，在tau病理和神经变性开始前后；2)在正常和人类tau转基因小鼠中，评估可能涉及tau周转的三个主要蛋白分解系统的功能：calain-calastatin、蛋白酶体和内体/溶酶体/自噬系统；3)确认 特异性蛋白分解系统在神经细胞tau周转和病理tau中的作用 人tau转基因小鼠体内蓄积。在时间允许的情况下，我们还将研究在htau小鼠身上叠加淀粉样蛋白b负荷后对轴突运输和蛋白分解的影响。

The abnormal accumulation of tau within the somatic dendritic compartment of neurons in Alzheimer's disease (AD) and other tauopathies is a hallmark neuropathologic lesion linked by still unknown mechanisms to neurodegeneration. Pathologic tau accumulation is likely to be related, in large part, to tau's posttranslational fate, but remarkably little is known about tau turnover or axonal transport in either normal neurons or in neuropathologic states. Moreover, adverse consequences of tau accumulation may well include secondary impairments of transport and activation of proteases leading to neurodegeneration. The overall goal of this proposal will be to provide fundamental information about the posttranslational behavior of tau by systematically analyzing the consequences of wild-type tau overexpression in neurons on axonal transport and on major proteolytic systems that may metabolize tau. These studies will specifically test the hypotheses that age-dependent alterations of tau proteolysis or axonal transport contribute to tau accumulation and that abnormal, proteolytic responses to tau accumulation/dysfunction promote neurodegeneration. To achieve these goals, we propose to: 1) evaluate the competency of the mechanisms for slow transport and fast transport, including tau transport, in wild-type mice and in a mouse model of tau-related neurodegeneration, which exhibits age-related tau accumulation and cell loss, before and after the onset of tau pathology and neurodegeneration; 2) assess the function of three major proteolytic systems potentially involved in tau turnover, the calpain-calpastatin, proteasome, and endosomal/lysosomal/autophagic systems, in normal and human tau transgenic mice; 3) confirm the role of specific proteolytic systems in tau turnover in neuronal cells and in pathologic tau accumulation in human tau transgenic mice in vivo. As time permits, we will also investigate effects on axonal transport and proteolysis after superimposing an amyloid-b burden on htau mice.