Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer’s disease

• Published in: Nature communications 2020-03, Vol.11 (1), p.1377-1377, Article 1377
• Main Authors: Kwak, Sang Su, Washicosky, Kevin J., Brand, Emma, von Maydell, Djuna, Aronson, Jenna, Kim, Susan, Capen, Diane E., Cetinbas, Murat, Sadreyev, Ruslan, Ning, Shen, Bylykbashi, Enjana, Xia, Weiming, Wagner, Steven L., Choi, Se Hoon, Tanzi, Rudolph E., Kim, Doo Yeon
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/31; 14/1; 14/19; 14/28; 14/35; 14/63; 38; 38/39; 38/90; 38/91; 631/1647/767/1658; 631/378/1689/1283; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid precursor protein; Biotechnology; Cell culture; Cell Culture Techniques - methods; Cell differentiation; Cells (biology); Cells, Cultured; Coculture Techniques; Humanities and Social Sciences; Humans; Isoforms; multidisciplinary; Mutants; Mutation; Neural stem cells; Neural Stem Cells - metabolism; Neurodegenerative diseases; Neurofibrillary tangles; Neurons - metabolism; Neurons - pathology; Pathology; Peptide Fragments - genetics; Peptide Fragments - metabolism; Presenilin 1; Presenilin-1 - genetics; Presenilin-1 - metabolism; Progenitor cells; Science; Science (multidisciplinary); Tau protein; Three dimensional models
• ISSN: 2041-1723; 2041-1723
• 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. The relationship between amyloid-β species and tau pathology in Alzheimer’s disease is not fully understood. Here, the authors show that it is the increased ratio of amyloid-β42 and 40 isoforms drives tau pathology in 3D human neural cell culture models of the disease.