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

Sang Su Kwak; Kevin J. Washicosky; Emma Brand; Djuna von Maydell; Jenna Aronson; Susan Kim; Diane E. Capen; Murat Cetinbas; Ruslan Sadreyev; Shen Ning; Enjana Bylykbashi; Weiming Xia; Steven L. Wagner; Se Hoon Choi; Rudolph E. Tanzi; Doo Yeon Kim

doi:10.1038/s41467-020-15120-3

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

Sang Su Kwak, Kevin J. Washicosky, Emma Brand, Djuna von Maydell, Jenna Aronson, Susan Kim, Diane E. Capen, Murat Cetinbas, Ruslan Sadreyev, Shen Ning, Enjana Bylykbashi, Weiming Xia, Steven L. Wagner, Se Hoon Choi, Rudolph E. Tanzi, Doo Yeon Kim

Houston Methodist

Research output: Contribution to journal › Article › peer-review

129 Scopus citations

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.

Original language	English (US)
Article number	1377
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15120-3
State	Published - Mar 13 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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Kwak, S. S., Washicosky, K. J., Brand, E., von Maydell, D., Aronson, J., Kim, S., Capen, D. E., Cetinbas, M., Sadreyev, R., Ning, S., Bylykbashi, E., Xia, W., Wagner, S. L., Choi, S. H., Tanzi, R. E., & Kim, D. Y. (2020). Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer’s disease. Nature Communications, 11(1), Article 1377. https://doi.org/10.1038/s41467-020-15120-3

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 & Kim, DY 2020, 'Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer’s disease', Nature Communications, vol. 11, no. 1, 1377. https://doi.org/10.1038/s41467-020-15120-3

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title = "Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer{\textquoteright}s disease",

abstract = "The relationship between amyloid-β (Aβ) species and tau pathology in Alzheimer{\textquoteright}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, na{\"i}ve 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.",

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AU - Aronson, Jenna

AU - Kim, Susan

AU - Capen, Diane E.

AU - Cetinbas, Murat

AU - Sadreyev, Ruslan

AU - Ning, Shen

AU - Bylykbashi, Enjana

AU - Xia, Weiming

AU - Wagner, Steven L.

AU - Choi, Se Hoon

AU - Tanzi, Rudolph E.

AU - Kim, Doo Yeon

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

Abstract

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