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A "multi-omics" analysis of blood–brain barrier and synaptic dysfunction in APOE4 mice

Barisano, Giuseppe and Kisler, Kassandra and Wilkinson, Brent and Nikolakopoulou, Angeliki Maria and Sagare, Abhay P. and Wang, Yaoming and Gilliam, William and Huuskonen, Mikko T. and Hung, Shu-Ting and Ichida, Justin K. and Gao, Fan and Coba, Marcelo P. and Zlokovic, Berislav V. (2022) A "multi-omics" analysis of blood–brain barrier and synaptic dysfunction in APOE4 mice. Journal of Experimental Medicine, 219 (11). Art. No. e20221137. ISSN 0022-1007. PMCID PMC9435921. doi:10.1084/jem.20221137. https://resolver.caltech.edu/CaltechAUTHORS:20221027-402241500.5

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Abstract

Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer’s disease, leads to blood–brain barrier (BBB) breakdown in humans and mice. Remarkably, BBB dysfunction predicts cognitive decline and precedes synaptic deficits in APOE4 human carriers. How APOE4 affects BBB and synaptic function at a molecular level, however, remains elusive. Using single-nucleus RNA-sequencing and phosphoproteome and proteome analysis, we show that APOE4 compared with APOE3 leads to an early disruption of the BBB transcriptome in 2–3-mo-old APOE4 knock-in mice, followed by dysregulation in protein signaling networks controlling cell junctions, cytoskeleton, clathrin-mediated transport, and translation in brain endothelium, as well as transcription and RNA splicing suggestive of DNA damage in pericytes. Changes in BBB signaling mechanisms paralleled an early, progressive BBB breakdown and loss of pericytes, which preceded postsynaptic interactome disruption and behavioral deficits that developed 2–5 mo later. Thus, dysregulated signaling mechanisms in endothelium and pericytes in APOE4 mice reflect a molecular signature of a progressive BBB failure preceding changes in synaptic function and behavior.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1084/jem.20221137DOIArticle
ORCID:
AuthorORCID
Barisano, Giuseppe0000-0001-5598-1369
Kisler, Kassandra0000-0002-4161-2498
Wilkinson, Brent0000-0001-7852-1218
Nikolakopoulou, Angeliki Maria0000-0002-1621-4965
Sagare, Abhay P.0000-0002-8178-3785
Wang, Yaoming0000-0002-6416-3445
Gilliam, William0000-0003-0266-3134
Huuskonen, Mikko T.0000-0002-7170-3016
Hung, Shu-Ting0000-0001-5629-945X
Ichida, Justin K.0000-0002-8827-8087
Gao, Fan0000-0001-6832-3402
Coba, Marcelo P.0000-0001-7075-6338
Zlokovic, Berislav V.0000-0002-6802-8232
Additional Information:We thank Lydia Lin for assistance with snRNA-seq data and Professor Christer Betsholtz and Dr. Liqun He for making available the single-cell RNA-seq data from their published mouse brain vascular atlas. The work of Berislav V. Zlokovic is supported by the National Institutes of Health grants 5P01AG052350 and R01NS034467, in addition to Cure Alzheimer’s Fund and the Foundation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease, reference no. 16CVD05. Author contributions: G. Barisano, K. Kisler, and B. Wilkinson contributed to data analysis and interpretation. W. Gilliam and G. Barisano processed the mouse brains and generated single nuclei preparations. G. Barisano and W. Gilliam prepared the snRNA-seq libraries, supported by S.-T. Hung and J.K. Ichida. F. Gao, G. Barisano, S.-T. Hung, K. Kisler, and J.K. Ichida analyzed the RNA-seq data. B. Wilkinson and M.P. Coba performed and analyzed phosphoproteomics, proteomics, and PSD95 interactome data. M.T. Huuskonen and G. Barisano performed MRI scans and analyzed MRI data. A.M. Nikolakopoulou performed all brain tissue assays. A.P. Sagare isolated microvessels and CD brains and performed staining and immunoblotting. Y. Wang performed behavioral tests and FISH analysis. G. Barisano, K. Kisler, B. Wilkinson, and F. Gao contributed to the manuscript writing. K. Kisler helped with final data analysis and careful reading, revision, and editing of the manuscript. M.P. Coba and B.V. Zlokovic designed the RNA-seq and proteomic study, supervised all data analysis and interpretation, and wrote the manuscript.
Funders:
Funding AgencyGrant Number
NIH5P01AG052350
NIHR01NS034467
Cure Alzheimer’s FundUNSPECIFIED
Foundation Leducq16CVD05
Issue or Number:11
PubMed Central ID:PMC9435921
DOI:10.1084/jem.20221137
Record Number:CaltechAUTHORS:20221027-402241500.5
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20221027-402241500.5
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:117632
Collection:CaltechAUTHORS
Deposited By: Research Services Depository
Deposited On:08 Nov 2022 19:36
Last Modified:08 Nov 2022 19:36

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