APOE4 derived from astrocytes leads to blood-brain barrier impairment

Rosemary J. Jackson, Jonah C. Meltzer, Huong Nguyen, Caitlin Commins, Rachel E. Bennett, Eloise Hudry, Bradley T. Hyman (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

69 Citations (Scopus)
4 Downloads (Pure)

Abstract

Apolipoprotein E (ApoE) is a multifaceted secreted molecule synthesized in the CNS by astrocytes and microglia, and in the periphery largely by the liver. ApoE has been shown to impact the integrity of the blood-brain barrier, and, in humans, the APOE4 allele of the gene is reported to lead to a leaky blood-brain barrier. We used allele specific knock-in mice expressing each of the common (human) ApoE alleles, and longitudinal multiphoton intravital microscopy, to directly monitor the impact of various ApoE isoforms on blood-brain barrier integrity. We found that humanized APOE4, but not APOE2 or APOE3, mice show a leaky blood-brain barrier, increased MMP9, impaired tight junctions, and reduced astrocyte end-foot coverage of blood vessels. Removal of astrocyte-produced ApoE4 led to the amelioration of all phenotypes while the removal of astrocyte-produced ApoE3 had no effect on blood-brain barrier integrity. This work shows a cell specific gain of function effect of ApoE4 in the dysfunction of the BBB and implicates astrocyte production of ApoE4, possibly as a function of astrocytic end foot interactions with vessels, as a key regulator of the integrity of the blood-brain barrier.

Original languageEnglish
Pages (from-to)3582-3593
Number of pages12
JournalBrain
Volume145
Issue number10
Early online date27 Dec 2021
DOIs
Publication statusPublished - Oct 2022

Keywords

  • Alzheimer's disease
  • apolipoprotein E
  • astrocytes
  • blood-brain barrier

ASJC Scopus subject areas

  • Clinical Neurology

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