CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice.
APOE
CCR5
Extracellular matrix
MMP
TIMP-1
Journal
Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
received:
06
10
2022
revised:
16
02
2023
accepted:
26
02
2023
pubmed:
7
3
2023
medline:
23
3
2023
entrez:
6
3
2023
Statut:
ppublish
Résumé
The APOE4 allele increases the risk for Alzheimer's disease (AD) in a dose-dependent manner and is also associated with cognitive decline in non-demented elderly controls. In mice with targeted gene replacement (TR) of murine APOE with human APOE3 or APOE4, the latter show reduced neuronal dendritic complexity and impaired learning. APOE4 TR mice also show reduced gamma oscillation power, a neuronal population activity which is important to learning and memory. Published work has shown that brain extracellular matrix (ECM) can reduce neuroplasticity as well as gamma power, while attenuation of ECM can instead enhance this endpoint. In the present study we examine human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 individuals and brain lysates from APOE3 and APOE4 TR mice for levels of ECM effectors that can increase matrix deposition and restrict neuroplasticity. We find that CCL5, a molecule linked to ECM deposition in liver and kidney, is increased in CSF samples from APOE4 individuals. Levels of tissue inhibitor of metalloproteinases (TIMPs), which inhibit the activity of ECM-degrading enzymes, are also increased in APOE4 CSF as well as astrocyte supernatants brain lysates from APOE4 TR mice. Importantly, as compared to APOE4/wild-type heterozygotes, APOE4/CCR5 knockout heterozygotes show reduced TIMP levels and enhanced EEG gamma power. The latter also show improved learning and memory, suggesting that the CCR5/CCL5 axis could represent a therapeutic target for APOE4 individuals.
Identifiants
pubmed: 36878326
pii: S0969-9961(23)00071-2
doi: 10.1016/j.nbd.2023.106057
pmc: PMC10291850
mid: NIHMS1906911
pii:
doi:
Substances chimiques
Apolipoprotein E4
0
Apolipoprotein E3
0
Apolipoproteins E
0
CCR5 protein, human
0
Receptors, CCR5
0
Banques de données
ClinicalTrials.gov
['NCT01504854']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
106057Subventions
Organisme : NIA NIH HHS
ID : R01 AG077002
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS100704
Pays : United States
Organisme : NINDS NIH HHS
ID : T32 NS121780
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG010483
Pays : United States
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest There are no competing financial interests for any of the authors in relation to the work described.
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