Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer's disease mutations.
App
NL-G-F/NL-G-F
5xFAD
Alzheimer’s disease
KCC2
chloride homeostasis
inhibition
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
01 Dec 2023
01 Dec 2023
Historique:
received:
12
05
2022
revised:
23
06
2023
accepted:
09
07
2023
medline:
4
12
2023
pubmed:
8
8
2023
entrez:
8
8
2023
Statut:
ppublish
Résumé
Disinhibition during early stages of Alzheimer's disease is postulated to cause network dysfunction and hyperexcitability leading to cognitive deficits. However, the underlying molecular mechanism remains unknown. Here we show that, in mouse lines carrying Alzheimer's disease-related mutations, a loss of neuronal membrane potassium-chloride cotransporter KCC2, responsible for maintaining the robustness of GABAA-mediated inhibition, occurs pre-symptomatically in the hippocampus and prefrontal cortex. KCC2 downregulation was inversely correlated with the age-dependent increase in amyloid-β 42 (Aβ42). Acute administration of Aβ42 caused a downregulation of membrane KCC2. Loss of KCC2 resulted in impaired chloride homeostasis. Preventing the decrease in KCC2 using long term treatment with CLP290 protected against deterioration of learning and cortical hyperactivity. In addition, restoring KCC2, using short term CLP290 treatment, following the transporter reduction effectively reversed spatial memory deficits and social dysfunction, linking chloride dysregulation with Alzheimer's disease-related cognitive decline. These results reveal KCC2 hypofunction as a viable target for treatment of Alzheimer's disease-related cognitive decline; they confirm target engagement, where the therapeutic intervention takes place, and its effectiveness.
Identifiants
pubmed: 37551444
pii: 7238625
doi: 10.1093/brain/awad250
pmc: PMC10690023
doi:
Substances chimiques
Chlorides
0
Amyloid beta-Peptides
0
Symporters
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4903-4915Subventions
Organisme : CIHR
ID : 159906
Pays : Canada
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.
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