淀粉样蛋白β42/40 比率驱动阿尔茨海默病 3D 人神经细胞培养模型中的 tau 病理学。
Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer's disease.
机构信息
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, McCance Center for Brain Health, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
出版信息
Nat Commun. 2020 Mar 13;11(1):1377. doi: 10.1038/s41467-020-15120-3.
The relationship between amyloid-β (Aβ) species and tau pathology in Alzheimer's disease (AD) is not fully understood. Here, we provide direct evidence that Aβ42/40 ratio, not total Aβ level, plays a critical role in inducing neurofibrillary tangles (NTFs) in human neurons. Using 3D-differentiated clonal human neural progenitor cells (hNPCs) expressing varying levels of amyloid β precursor protein (APP) and presenilin 1 (PS1) with AD mutations, we show that pathogenic tau accumulation and aggregation are tightly correlated with Aβ42/40 ratio. Roles of Aβ42/40 ratio on tau pathology are also confirmed with APP transmembrane domain (TMD) mutant hNPCs, which display differential Aβ42/40 ratios without mutant PS1. Moreover, naïve hNPCs co-cultured with APP TMD I45F (high Aβ42/40) cells, not with I47F cells (low Aβ42/40), develop robust tau pathology in a 3D non-cell autonomous cell culture system. These results emphasize the importance of reducing the Aβ42/40 ratio in AD therapy.
淀粉样蛋白-β（Aβ）物种与阿尔茨海默病（AD）中的 tau 病理学之间的关系尚未完全阐明。在这里，我们提供了直接证据，表明 Aβ42/40 比值而非总 Aβ 水平在诱导人神经元神经原纤维缠结（NTFs）中起着关键作用。使用表达不同水平淀粉样前体蛋白（APP）和早老素 1（PS1）的具有 AD 突变的 3D 分化克隆人神经祖细胞（hNPC），我们表明致病性 tau 积累和聚集与 Aβ42/40 比值密切相关。使用具有 APP 跨膜结构域（TMD）突变的 hNPC 也证实了 Aβ42/40 比值对 tau 病理学的作用，这些细胞显示出没有突变 PS1 的差异 Aβ42/40 比值。此外，在 3D 非细胞自主细胞培养系统中，与 APP TMD I45F（高 Aβ42/40）细胞共培养而不是与 I47F 细胞（低 Aβ42/40）共培养的未成熟 hNPC 会发展出强大的 tau 病理学。这些结果强调了在 AD 治疗中降低 Aβ42/40 比值的重要性。
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