敲除鼠 tau 基因增加了人类突变 tau 转基因小鼠模型中的 tau 聚集。

Deletion of murine tau gene increases tau aggregation in a human mutant tau transgenic mouse model.

机构信息

Laboratory of Histology, Neuroanatomy and Neuropathology, Université Libre de Bruxelles, 808 route de Lennik, B-1070 Brussels, Belgium.

出版信息

Biochem Soc Trans. 2010 Aug;38(4):1001-5. doi: 10.1042/BST0381001.

DOI:10.1042/BST0381001

PMID:20658993

Abstract

We have reported previously a tau transgenic mouse model (Tg30tau) overexpressing human 4R1N double-mutant tau (P301S and G272V) and that develops AD (Alzheimer's disease)-like NFTs (neurofibrillary tangles) in an age-dependent manner. Since murine tau might interfere with the toxic effects of human mutant tau, we set out to analyse the phenotype of our Tg30tau model in the absence of endogenous murine tau with the aim to reproduce more faithfully a model of human tauopathy. By crossing the Tg30tau line with TauKO (tau-knockout) mice, we have obtained a new mouse line called Tg30xTauKO that expresses only exogenous human double-mutant 4R1N tau. Whereas Tg30xTauKO mice express fewer tau proteins compared with Tg30tau, they exhibit augmented sarkosyl-insoluble tau in the brain and an increased number of Gallyas-positive NFTs in the hippocampus. Taken together, exclusion of murine tau causes accelerated tau aggregation during aging of this mutant tau transgenic model.

摘要

我们之前曾报道过一种过度表达人类 4R1N 双突变 tau（P301S 和 G272V）的 tau 转基因小鼠模型（Tg30tau），该模型以年龄依赖的方式出现类似于 AD（阿尔茨海默病）的 NFT（神经纤维缠结）。由于鼠 tau 可能会干扰人突变 tau 的毒性作用，我们着手分析 Tg30tau 模型在没有内源性鼠 tau 的情况下的表型，旨在更忠实地复制人类 tau 病模型。通过将 Tg30tau 系与 TauKO（tau 敲除）小鼠杂交，我们获得了一种称为 Tg30xTauKO 的新小鼠系，该小鼠仅表达外源性人双突变 4R1N tau。虽然与 Tg30tau 相比，Tg30xTauKO 小鼠表达的 tau 蛋白较少，但它们在大脑中显示出更多的 Sarkosyl 不溶性 tau，并且在海马体中出现更多的 Gallyas 阳性 NFT。总之，在这种突变 tau 转基因模型衰老过程中，排除鼠 tau 会导致 tau 聚集加速。