A “multi-omics” analysis of blood–brain barrier and synaptic dysfunction in APOE4 mice
Open accessAbstract
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.
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APOE4 is associated with reduced neuronal and synaptic expression of ATP1A1 (Na+/K+-ATPase α1) in cortical excitatory neurons and the PSD95 interactome.
“our analysis of the publicly available synaptic interactome and single-nucleus RNA sequencing (snRNA-Seq) data (Barisano et al., 2022) revealed that APOE4 is associated with reduced neuronal and synaptic expression of ATP1A1”
From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Barisano et al., 2022
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ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
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- Authors
- Barisano, G., Kisler, K., Wilkinson, B., Nikolakopoulou, A. M., Sagare, A. P., Wang, Y., Gilliam, W., Huuskonen, M. T., Hung, S.-T., Ichida, J. K., Gao, F., Coba, M. P., & Zlokovic, B. V.
- Affiliations
- University of Southern California (US)
- California Institute of Technology (US)
- Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 1
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2022-08-30
- Volume
- 219
- Issue
- 11
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC9435921
- OpenAlex
- W4293574716
- Cited by
- 78
- References
- 24
- Citations by year
- 2026: 17 · 2025: 24 · 2024: 18 · 2023: 17 · 2022: 2
- FWCI
- 5.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- National Institutes of Health (5P01AG052350, R01NS034467)
- Cure Alzheimer’s Fund
- Foundation Leducq (16CVD05)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APOE ε4, blood-brain barrier disruption, synaptic dysfunction, Alzheimer's disease, brain endothelium, pericytes, cell junctions, RNA splicing, DNA damage, cognitive decline, single-nucleus RNA sequencing, phosphoproteomics, proteomics
- MeSH terms
- Alzheimer Disease, Animals, Blood-Brain Barrier, Humans, Mice, Transgenic, Pericytes, Mice, Apolipoprotein E3, Apolipoprotein E4
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