Switch to phagocytic microglia by CSFR1 inhibition drives amyloid-beta clearance from glutamatergic terminals rescuing LTP in acute hippocampal slices.
Transl Psychiatry
; 14(1): 338, 2024 Aug 23.
Article
em En
| MEDLINE
| ID: mdl-39179543
ABSTRACT
Microglia, traditionally regarded as innate immune cells in the brain, drive neuroinflammation and synaptic dysfunctions in the early phases of Alzheimer disease (AD), acting upstream to Aß accumulation. Colony stimulating factor 1-receptor (CSF-1R) is predominantly expressed on microglia and its levels are significantly increased in neurodegenerative diseases, possibly contributing to the chronic inflammatory microglial response. On the other hand, CSF-1R inhibitors confer neuroprotection in preclinical models of neurodegenerative diseases. Here, we determined the effects of the CSF-1R inhibitor PLX3397 on the Aß-mediated synaptic alterations in ex vivo hippocampal slices. Electrophysiological findings show that PLX3397 rescues LTP impairment and neurotransmission changes induced by Aß. In addition, using confocal imaging experiments, we demonstrate that PLX3397 stimulates a microglial transition toward a phagocytic phenotype, which in turn promotes the clearance of Aß from glutamatergic terminals. We believe that the selective pruning of Aß-loaded synaptic terminals might contribute to the restoration of LTP and excitatory transmission alterations observed upon acute PLX3397 treatment. This result is in accordance with the mechanism proposed for CSF1R inhibitors, that is to eliminate responsive microglia and replace it with newly generated, homeostatic microglia, capable of promoting brain repair. Overall, our findings identify a connection between the rapid microglia adjustments and the early synaptic alterations observed in AD, possibly highlighting a novel disease-modifying target.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
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Microglia
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Potenciação de Longa Duração
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Aminopiridinas
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Hipocampo
Limite:
Animals
Idioma:
En
Revista:
Transl Psychiatry
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Itália
País de publicação:
Estados Unidos