1. Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer's disease.
- Author
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Kwak SS, Washicosky KJ, Brand E, von Maydell D, Aronson J, Kim S, Capen DE, Cetinbas M, Sadreyev R, Ning S, Bylykbashi E, Xia W, Wagner SL, Choi SH, Tanzi RE, and Kim DY
- Subjects
- Alzheimer Disease diagnostic imaging, Alzheimer Disease genetics, Amyloid beta-Peptides genetics, Cells, Cultured, Coculture Techniques, Humans, Mutation, Neural Stem Cells metabolism, Peptide Fragments genetics, Presenilin-1 genetics, Presenilin-1 metabolism, Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Peptides metabolism, Cell Culture Techniques methods, Neurons metabolism, Neurons pathology, Peptide Fragments metabolism
- Abstract
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.
- Published
- 2020
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