Microglial polarization differentially affects neuronal vulnerability to the ß-amyloid protein: Modulation by melatonin.
Biochem Pharmacol
; 202: 115151, 2022 08.
Article
em En
| MEDLINE
| ID: mdl-35750198
ABSTRACT
Microglial cells play a central but yet debated role in neuroinflammatory events occurring in Alzheimer's disease (AD). We here explored how microglial features are modulated by melatonin following ß-amyloid (Aß42)-induced activation and examined the cross-talk with Aß-challenged neuronal cells. Human microglial HMC3 cells were exposed to Aß42 (200 nM) in the presence of melatonin (MEL; 1 µM) added since the beginning (MELco) or after a 72 h-exposure to Aß42 (MELpost). In both conditions, MEL favored an anti-inflammatory activation and rescued SIRT1 and BDNF expression/release. Caspase-1 up-regulation and phospho-ERK induction following a prolonged exposure to Aß42 were prevented by MEL. In addition, MEL partially restored proteasome functionality that was altered by long-term Aß42 treatment, re-establishing both 20S and 26S chymotrypsin-like activity. Differentiated neuronal-like SH-SY5Y cells were exposed to Aß42 (200 nM for 24 h) in basal medium or in the presence of conditioned medium (CM) collected from microglia exposed for different times to Aß42 alone or in combination with MELco or MELpost. Aß42 significantly reduced pre-synaptic proteins synaptophysin and VAMP2 and mean neuritic length. These effects were prevented by CM from anti-inflammatory microglia (Aß42 for 6 h), or from MELco and MELpost microglia, but the reduction of neuritic length was not rescued when the SIRT1 inhibitor EX527 was added. In conclusion, our data add to the concept that melatonin shows a promising anti-inflammatory action on microglia that is retained even after pro-inflammatory activation, involving modulation of proteasome function and translating into neuroprotective microglial effects.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fármacos Neuroprotetores
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Doença de Alzheimer
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Melatonina
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Neuroblastoma
Limite:
Humans
Idioma:
En
Revista:
Biochem Pharmacol
Ano de publicação:
2022
Tipo de documento:
Article