Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer's disease
Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer's disease
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DOI：
10.1038/s41467-020-15120-3
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发表时间：
2020-03-13
影响因子：
16.6
通讯作者：
Kim, Doo Yeon
中科院分区：
文献类型：
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作者：
Kwak, Sang Su;Washicosky, Kevin J.;Kim, Doo Yeon
淀粉样蛋白-β（A β）种类和阿尔茨海默病（AD）中的tau病理学之间的关系尚未完全了解。在这里，我们提供了直接的证据表明，A β 42/40的比例，而不是总的A β水平，在诱导人类神经元神经元缠结（NTFs）中起着关键作用。使用3D分化的克隆人神经祖细胞（hNPC）表达不同水平的淀粉样β前体蛋白（APP）和早老素1（PS1）与AD突变，我们发现致病性tau蛋白的积累和聚集与A β 42/40比率密切相关。A β 42/40比率对tau病理学的作用也用APP跨膜结构域（TMD）突变体hNPC证实，其在没有突变体PS1的情况下显示出不同的A β 42/40比率。此外，与APP TMD I45 F（高A β 42/40）细胞而不是与I47 F细胞（低A β 42/40）共培养的幼稚hNPC在3D非细胞自主细胞培养系统中发展出稳健的tau病理学。这些结果强调了在AD治疗中降低A β 42/40比率的重要性。
The relationship between amyloid-beta (A beta) species and tau pathology in Alzheimer's disease (AD) is not fully understood. Here, we provide direct evidence that A beta 42/40 ratio, not total A beta 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 beta precursor protein (APP) and presenilin 1 (PS1) with AD mutations, we show that pathogenic tau accumulation and aggregation are tightly correlated with A beta 42/40 ratio. Roles of A beta 42/40 ratio on tau pathology are also confirmed with APP transmembrane domain (TMD) mutant hNPCs, which display differential A beta 42/40 ratios without mutant PS1. Moreover, naive hNPCs co-cultured with APP TMD I45F (high A beta 42/40) cells, not with I47F cells (low A beta 42/40), develop robust tau pathology in a 3D non-cell autonomous cell culture system. These results emphasize the importance of reducing the A beta 42/40 ratio in AD therapy.