APOE4 derived from astrocytes leads to blood-brain barrier impairment.
Alzheimer's disease
apolipoprotein E
astrocytes
blood–brain barrier
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
21 10 2022
21 10 2022
Historique:
received:
20
07
2021
revised:
25
10
2021
accepted:
01
12
2021
pubmed:
28
12
2021
medline:
26
10
2022
entrez:
27
12
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34957486
pii: 6484505
doi: 10.1093/brain/awab478
pmc: PMC9586546
doi:
Substances chimiques
Apolipoprotein E4
0
Apolipoprotein E3
0
Matrix Metalloproteinase 9
EC 3.4.24.35
Protein Isoforms
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3582-3593Subventions
Organisme : NIA NIH HHS
ID : T32 AG000222
Pays : United States
Organisme : NIA NIH HHS
ID : K99 AG061259
Pays : United States
Organisme : NIA NIH HHS
ID : R00 AG047336
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG047644
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.
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