Abstract
Vascular endothelial cells play an important role in maintaining brain health, but their contribution to Alzheimer’s disease (AD) is obscured by limited understanding of the cellular heterogeneity in normal aged brain and in disease. To address this, we performed single nucleus RNAseq on tissue from 32 human AD and non-AD donors (19 female, 13 male) each with five cortical regions: entorhinal cortex, inferior temporal gyrus, prefrontal cortex, visual association cortex and primary visual cortex. Analysis of 51,586 endothelial cells revealed unique gene expression patterns across the five regions in non-AD donors. Alzheimer’s brain endothelial cells were characterized by upregulated protein folding genes and distinct transcriptomic differences in response to amyloid beta plaques and cerebral amyloid angiopathy (CAA). This dataset demonstrates previously unrecognized regional heterogeneity in the endothelial cell transcriptome in both aged non-AD and AD brain.
SIGNIFICANCE STATEMENT:
In this work, we show that vascular endothelial cells collected from five different brain regions display surprising variability in gene expression. In the presence of Alzheimer's disease pathology, endothelial cell gene expression is dramatically altered with clear differences in regional and temporal changes. These findings help explain why certain brain regions appear to differ in susceptibility to disease-related vascular remodeling events that may impact blood flow.
Footnotes
MEW, AW, GL, TK, RVT, KB and EHK are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. BTH has received research funding from AbbVie as part of a collaboration agreement with The General Hospital Corporation, d/b/a Massachusetts General Hospital. BTH has a family member who works at Novartis and owns stock in Novartis; he serves on the SAB of Dewpoint and owns stock. He serves on a scientific advisory board or is a consultant for AbbVie, Avrobio, Axon, Biogen, BMS Cell Signaling, Genentech, Ionis, Novartis, Seer, Takeda, the US Dept of Justice, Vigil, Voyager. His laboratory is supported by Sponsored research agreements with AbbVie, F Prime, and research grants from the National Institutes of Health, Cure Alzheimer’s Fund, Tau Consortium, and the JPB Foundation. AB, ZL, ASP, SD, and RB work on the AbbVie-Hyman Collaboration and have no other funding to disclose.
This work was supported by NIH grants R01AG071567 (Bennett), P30AG062421 (Hyman and Das), K08AG064039 (Serrano-Pozo) and MASSCATS. We would like to acknowledge individuals who have assisted in completing this project including Patrick Dooley and Teresa Connors for their help with tissue selection, Derek Oakley and Matthew Frosch for their neuropathological expertise, and Simon Dujardin and Sarah Hopp for their intellectual support. We also thank the many donors and their families who have contributed to the Massachusetts Alzheimer’s Disease Research Center.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
