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

Research output: Contribution to journal › Article

12 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

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

Access to Document

10.1038/s41467-020-15120-3

Fingerprint Dive into the research topics of 'Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer’s disease'. Together they form a unique fingerprint.

Cite this

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), [1377]. https://doi.org/10.1038/s41467-020-15120-3

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

In: Nature Communications, Vol. 11, No. 1, 1377, 13.03.2020.

Research output: Contribution to journal › Article

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

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. / Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer’s disease. In: Nature Communications. 2020 ; Vol. 11, No. 1.

@article{8d64007fa4d840d6953cbc98c29f6bcc,

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.",

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

year = "2020",

month = mar,

day = "13",

doi = "10.1038/s41467-020-15120-3",

language = "English (US)",

volume = "11",

journal = "Nat Commun",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer’s disease

AU - Kwak, Sang Su

AU - Washicosky, Kevin J.

AU - Brand, Emma

AU - von Maydell, Djuna

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

PY - 2020/3/13

Y1 - 2020/3/13

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85081736158&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85081736158&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-15120-3

DO - 10.1038/s41467-020-15120-3

M3 - Article

C2 - 32170138

AN - SCOPUS:85081736158

VL - 11

JO - Nat Commun

JF - Nat Commun

SN - 2041-1723

IS - 1

M1 - 1377

ER -