Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) plaques and intracellular tau inclusions. However, the exact mechanistic link between these two AD lesions remains enigmatic. Through injection of human AD-brain-derived pathological tau (AD-tau) into Aβ plaque-bearing mouse models that do not overexpress tau, we recapitulated the formation of three major types of AD-relevant tau pathologies: tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau), AD-like neurofibrillary tangles (NFTs) and neuropil threads (NTs). These distinct tau pathologies have different temporal onsets and functional consequences on neural activity and behavior. Notably, we found that Aβ plaques created a unique environment that facilitated the rapid amplification of proteopathic AD-tau seeds into large tau aggregates, initially appearing as NP tau, which was followed by the formation and spread of NFTs and NTs, likely through secondary seeding events. Our study provides insights into a new multistep mechanism underlying Aβ plaque-associated tau pathogenesis.

中文翻译：

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β 淀粉样蛋白斑块通过促进神经炎斑块 tau 蛋白聚集来增强阿尔茨海默病脑部 tau 种子病理学。

阿尔茨海默病 (AD) 的特征是细胞外淀粉样蛋白-β (Aβ) 斑块和细胞内 tau 包含物。然而，这两种 AD 病变之间的确切机制联系仍然是个谜。通过将人 AD 脑源性病理性 tau (AD-tau) 注射到不过度表达 tau 的 Aβ 斑块小鼠模型中，我们概括了 AD 相关 tau 病理的三种主要类型的形成： Aβ 斑块 (NP tau)、AD 样神经原纤维缠结 (NFT) 和神经纤维丝 (NT)。这些不同的 tau 蛋白病理学对神经活动和行为具有不同的时间发作和功能后果。值得注意的是，我们发现 Aβ 斑块创造了一个独特的环境，有利于蛋白病 AD-tau 种子快速扩增成大的 tau 聚集体，最初以 NP tau 形式出现，随后可能通过二次播种形成和传播 NFT 和 NT事件。我们的研究提供了对 Aβ 斑块相关 tau 发病机制的新多步骤机制的见解。