Aβ加速了 tau 病理的时空进展,并增强了阿尔茨海默病小鼠模型中的 tau 淀粉样变性。

A{beta} accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model.

机构信息

Department of Pathology, Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283, USA.

出版信息

Am J Pathol. 2010 Oct;177(4):1977-88. doi: 10.2353/ajpath.2010.100346. Epub 2010 Aug 27.

Abstract

Senile plaques formed by β-amyloid peptides (Aβ) and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau, a microtubule-associated protein, are the hallmark lesions of Alzheimer's disease (AD) in addition to loss of neurons. While several transgenic (Tg) mouse models have recapitulated aspects of AD-like Aβ and tau pathologies, a spatiotemporal mapping paradigm for progressive NFT accumulation is urgently needed to stage disease progression in AD mouse models. Braak and co-workers developed an effective and widely used NFT staging paradigm for human AD brains. The creation of a Braak-like spatiotemporal staging scheme for tau pathology in mouse models would facilitate mechanistic studies of AD-like tau pathology. Such a scheme would also enhance the reproducibility of preclinical AD therapeutic studies. Thus, we developed a novel murine model of Aβ and tau pathologies and devised a spatiotemporal scheme to stage the emergence and accumulation of NFTs with advancing age. Notably, the development of NFTs followed a spatiotemporal Braak-like pattern similar to that observed in authentic AD. More significantly, the presence of Aβ accelerated NFT formation and enhanced tau amyloidosis; however, tau pathology did not have the same effect on Aβ pathology. This novel NFT staging scheme provides new insights into the mechanisms of tau pathobiology, and we speculate that this scheme will prove useful for other basic and translational studies of AD mouse models.

摘要

除了神经元丧失之外,β-淀粉样肽(Aβ)形成的老年斑和微管相关蛋白过度磷酸化的 tau 形成的神经原纤维缠结(NFT)是阿尔茨海默病(AD)的标志性病变。虽然几种转基因(Tg)小鼠模型已经重现了 AD 样 Aβ和 tau 病理学的某些方面,但迫切需要一种 NFT 累积的时空映射范式来分期 AD 小鼠模型中的疾病进展。Braak 及其同事为人类 AD 大脑开发了一种有效的、广泛使用的 NFT 分期范式。在 AD 样 tau 病理学的小鼠模型中创建类似于 Braak 的时空分期方案将有助于 AD 样 tau 病理学的机制研究。这样的方案还将提高 AD 前临床治疗研究的可重复性。因此,我们开发了一种新的 Aβ和 tau 病理学的小鼠模型,并设计了一种时空方案来分期 NFT 的出现和随年龄增长的积累。值得注意的是,NFT 的发展遵循类似于在真实 AD 中观察到的时空 Braak 样模式。更重要的是,Aβ的存在加速了 NFT 的形成并增强了 tau 淀粉样变性;然而,tau 病理学对 Aβ病理学没有相同的影响。这种新的 NFT 分期方案为 tau 病理生物学的机制提供了新的见解,我们推测该方案将对 AD 小鼠模型的其他基础和转化研究有用。

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