Endothelial Cells Are Heterogeneous in Different Brain Regions and Are Dramatically Altered in Alzheimer's Disease
- Annie Bryant1,
- Zhaozhi Li1,
- Rojashree Jayakumar1,
- Alberto Serrano-Pozo1,
- Benjamin Woost1,
- Miwei Hu1,
- Maya E. Woodbury2,
- Astrid Wachter3,
- Gen Lin3,
- Taekyung Kwon2,
- Robert V. Talanian2,
- Knut Biber3,
- Eric H. Karran2,
- Bradley T. Hyman1,
- Sudeshna Das1, and
- Rachel E. Bennett1
- 1Department of Neurology, Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129
- 2AbbVie, Cambridge Research Center, Cambridge, Massachusetts 02139
- 3AbbVie Deutschland GmbH & Company KG, Genomics Research Center, Ludwigshafen, 67061, Germany
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Author contributions: A.B., A.S.-P., M.E.W., A.W., B.T.H., S.D., and R.E.B. designed research; A.B., A.S.-P., B.W., M.H., M.E.W., A.W., G.L., T.K., S.D., and R.E.B. performed research; A.B., Z.L., R.J., A.W., S.D., and R.E.B. analyzed data; A.B. and R.E.B. wrote the first draft of the paper; A.B., Z.L., R.J., A.S.-P., B.W., M.H., M.E.W., A.W., G.L., T.K., R.V.T., K.B., E.H.K., B.T.H., S.D., and R.E.B. edited the paper; A.B. and R.E.B. wrote the paper.
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 β plaques and cerebral amyloid angiopathy. 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.
- Received February 16, 2023.
- Revision received May 9, 2023.
- Accepted May 11, 2023.
- Copyright © 2023 Bryant et al.
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.
