Amyloid and tau pathology in a transgenic model

描述(申请人提供)：我们最近开发了一种通过表达突变型tau(P301L)来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的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。这是迄今为止发表的唯一一种同时出现淀粉样斑块和缠结的小鼠模型。更重要的是，TAPP小鼠提供了证据，证明APP/Abeta与tau相互作用，在这些小鼠的脆弱区域引起强化的NFT病理。在这项建议中，我们的目标是研究这种相互作用的性质，并通过将tau(P301L)小鼠与TgCRND8 APP小鼠杂交来产生改进的tau/app小鼠模型。这项应用有四个特定的目标：在目标1中，我们将研究过度磷酸化的tau在TAPP小鼠中的积累，以确定特定激酶的激活是否可以解释这些小鼠边缘NFT增强的病理。在目标2中，AP疫苗将被用作防止TAPP小鼠淀粉样蛋白沉积的工具，以确定AI3清除是否也会阻止皮质边缘NFT的形成。在目标3中，我们计划通过将tau(P301L)小鼠与第二个突变的APP小鼠TgCRND8(由Westaway博士培育)杂交，在TAPP小鼠中复制和扩展我们的发现。TgCRND8小鼠在3个月大时出现淀粉样沉积，因此这一tau/app小鼠模型将确定加速的淀粉样沉积是否也会导致皮质边缘NFT病理的加速和更广泛的形成。最后，在目标4中，将用Abeta免疫tau(P301L)/TgCRND8小鼠，以确定预防和清除淀粉样病变是否会阻止NFT的形成，并改善有斑块和缠结的小鼠的认知功能。

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.