Amyloid and tau pathology in a transgenic model

描述（由申请人提供）：我们最近开发了一种通过表达突变tau （P301L）形成神经原纤维缠结的转基因小鼠模型。当该小鼠模型与突变体APP转基因小鼠Tg2576杂交时，双转基因后代（TAPP）出现淀粉样斑块，并增强边缘NFT病理。这是迄今为止唯一发表的同时产生淀粉样斑块和缠结的小鼠模型。更重要的是，TAPP小鼠提供了APP/ beta与tau相互作用导致这些小鼠易感区域NFT病理增强的证据。在本提案中，我们旨在研究这种相互作用的性质，并通过将tau（P301L）小鼠与TgCRND8 APP小鼠杂交来生成改进的tau/APP小鼠模型。该应用程序有四个特定目的：在目的1中，我们将研究TAPP小鼠中过度磷酸化tau的积累，以确定特定激酶的激活是否可以解释这些小鼠中边缘NFT病理的增强。在Aim 2中，Ap疫苗接种将被用作防止TAPP小鼠淀粉样蛋白沉积的工具，以确定AI3清除是否也会阻断皮质边缘NFT的形成。在aims 3中，我们计划通过将tau（P301L）小鼠杂交到第二个突变的APP小鼠TgCRND8（由Westaway博士产生），在TAPP小鼠中复制并扩展我们的发现。TgCRND8小鼠在3个月大时发生淀粉样蛋白沉积，因此tau/APP小鼠模型将确定淀粉样蛋白沉积加速是否也会导致皮质边缘NFT病理加速和更广泛的形成。最后，在Aim 4中，将用Abeta免疫tau(P301L)/TgCRND8小鼠，以确定淀粉样蛋白病理的预防和清除是否会阻断NFT的形成，并改善斑块和缠结小鼠的认知功能。

DESCRIPTION (provided by applicant): We recently developed a transgenic mouse model of neurofibrillary tangle formation by expressing mutant tau (P301L). When this mouse model is crossed with mutant APP transgenic mice (Tg2576), the double transgenic progeny (TAPP) develop amyloid plaques and enhanced limbic NFT pathology. This is the only published mouse model to date that develops both amyloid plaques and tangles. More importantly the TAPP mice provide evidence that APP/Abeta interacts with tau to cause enhanced NFT pathology in vulnerable regions in these mice. In this proposal we aim to investigate the nature of this interaction and also to generate an improved tau/APP mouse model by crossing the tau(P301L) mice to TgCRND8 APP mice. The application has four Specific Aims: In Aim 1, we will investigate the accumulation of hyperphosphorylated tau in the TAPP mice to determine if activation of specific kinases might explain the enhanced limbic NFT pathology in these mice. In Aim 2, Ap vaccination will be used as a tool to prevent amyloid deposition in the TAPP mice to determine if AI3 clearance will also block cortico-limbic NFT formation. In Aim 3, we plan to replicate and extend our findings in the TAPP mice by crossing the tau(P301L) mice to a second mutant APP mouse, TgCRND8 (generated by Dr Westaway). The TgCRND8 mice develop amyloid deposition by 3 months of age and thus this tau/APP mouse model will determine if accelerated amyloid deposition will also cause accelerated and more extensive formation of cortico-limbic NFT pathology. Last in Aim 4, the tau(P301L)/TgCRND8 mice will be immunized with Abeta to determine if prevention and clearance of amyloid pathology will block NFT formation and improve cognitive function in mice with plaques and tangles.