@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}",
note = "Funding Information: This work is supported by the grants from the Cure Alzheimer{\textquoteright}s fund (D.Y.K. and R.E.T.), the JPB Foundation (R.E.T.), and National Institute of Health grants: 1RF1AG048080-01 (D.Y.K. and R.E.T.), 5P01AG15379 (D.Y.K. and R.E.T.), 2R01AG014713 (D.Y.K.) and 5R37MH060009 (R.E.T.). We appreciate Drs. Michael Wolfe (University of Kansas) and Dennis J. Selkoe (Brigham and Women{\textquoteright}s Hospital) for their helpful advice and providing reference APP TMD plasmids. We also appreciate Dr. Peter Davies (Albert Einstein College of Medicine, Bronx, USA) for providing PHF1, Alz50 and MC1 tau antibodies. We would like to thank Ms. Adalis Maisonet and Mr. Ulandt Kim at MGH Next Generation Sequencing Core for the technical assistance. We also appreciate Dr. Wilma Wasco (Massachusetts General Hospital, Boston, USA) for revising the manuscript. Electron microscopy was performed in the Microscopy Core of the Center for Systems Biology/Program in Membrane Biology, which is partially supported by an Inflammatory Bowel Disease Grant DK043351 and a Boston Area Diabetes and Endocrinology Research Center (BADERC) Award DK057521. Cytometric findings reported here were performed in the MGH Department of Pathology Flow and Image Cytometry Research Core, which obtained support from the NIH Shared Instrumentation program with grants 1S10OD012027-01A1, 1S10OD016372-01, 1S10RR020936-01, and 1S10RR023440-01. Lentiviral packaging was performed at MGH Viral Vector Core (supported by NIH/NINDS P30NS04776, PI Dr. Bakhos A. Tannos). Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = mar,
day = "13",
doi = "10.1038/s41467-020-15120-3",
language = "English (US)",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Research",
number = "1",
}