Genetic deletion of astrocytic calcineurin B1 prevents cognitive impairment and neuropathology development in acute and chronic mouse models of Alzheimer's disease.
Alzheimer's disease
astrocytes
calcineurin B1
memory
neuroinflammation
therapy
β-amyloid oligomers
Journal
Glia
ISSN: 1098-1136
Titre abrégé: Glia
Pays: United States
ID NLM: 8806785
Informations de publication
Date de publication:
May 2024
May 2024
Historique:
revised:
15
01
2024
received:
21
06
2023
accepted:
18
01
2024
pubmed:
30
1
2024
medline:
30
1
2024
entrez:
30
1
2024
Statut:
ppublish
Résumé
Alzheimer's disease (AD) represents an urgent yet unmet challenge for modern society, calling for exploration of innovative targets and therapeutic approaches. Astrocytes, main homeostatic cells in the CNS, represent promising cell-target. Our aim was to investigate if deletion of the regulatory CaNB1 subunit of calcineurin in astrocytes could mitigate AD-related memory deficits, neuropathology, and neuroinflammation. We have generated two, acute and chronic, AD mouse models with astrocytic CaNB1 ablation (ACN-KO). In the former, we evaluated the ability of β-amyloid oligomers (AβOs) to impair memory and activate glial cells once injected in the cerebral ventricle of conditional ACN-KO mice. Next, we generated a tamoxifen-inducible astrocyte-specific CaNB1 knock-out in 3xTg-AD mice (indACNKO-AD). CaNB1 was deleted, by tamoxifen injection, in 11.7-month-old 3xTg-AD mice for 4.4 months. Spatial memory was evaluated using the Barnes maze; β-amyloid plaques burden, neurofibrillary tangle deposition, reactive gliosis, and neuroinflammation were also assessed. The acute model showed that ICV injected AβOs in 2-month-old wild type mice impaired recognition memory and fostered a pro-inflammatory microglia phenotype, whereas in ACN-KO mice, AβOs were inactive. In indACNKO-AD mice, 4.4 months after CaNB1 depletion, we found preservation of spatial memory and cognitive flexibility, abolishment of amyloidosis, and reduction of neurofibrillary tangles, gliosis, and neuroinflammation. Our results suggest that ACN is crucial for the development of cognitive impairment, AD neuropathology, and neuroinflammation. Astrocyte-specific CaNB1 deletion is beneficial for both the abolishment of AβO-mediated detrimental effects and treatment of ongoing AD-related pathology, hence representing an intriguing target for AD therapy.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
899-915Subventions
Organisme : Università degli Studi del Piemonte Orientale
ID : FAR-2016
Organisme : Università degli Studi del Piemonte Orientale
ID : FAR-2019
Organisme : Fondazione CRT
ID : 1393-2017
Organisme : Fondazione Cariplo
ID : 2014-1094
Informations de copyright
© 2024 Wiley Periodicals LLC.
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