SIRT1-Dependent Upregulation of BDNF in Human Microglia Challenged with Aß: An Early but Transient Response Rescued by Melatonin.
Biomedicines
; 9(5)2021 Apr 24.
Article
in En
| MEDLINE
| ID: mdl-33923297
ABSTRACT
Microglia represent a first-line defense in the brain. However, in pathological conditions such as Alzheimer's disease (AD), a pro-inflammatory switch may occur, leading to loss of protective functions. Using the human microglial cell line HMC3, we showed that exposure to low concentrations of ß-amyloid peptide 1-42 (Aß42; 0.2 µM) initially (6 h) upregulated anti-inflammatory markers interleukin (IL)-4, IL-13, and brain-derived neurotrophic factor (BDNF). BDNF increase was prevented by selective inhibition of SIRT1 with EX527 (2 µM). Accordingly, these early effects were accompanied by a significant Aß42-induced increase of SIRT1 expression, nuclear localization, and activity. SIRT1 modulation involved adenosine monophosphate-regulated kinase (AMPK), which was promptly (30 min) phosphorylated by Aß42, while the AMPK inhibitor BML-275 (2 µM) attenuated Aß42-induced SIRT1 increase. Initially observed microglial responses appeared transient, as microglial features changed when exposure to Aß42 was prolonged (0.2 µM for 72 h). While SIRT1 and BDNF levels were reduced, the expression of inflammatory markers IL-1ß and tumor necrosis factor (TNF)-α increased. This coincided with a rise in NF-kB nuclear localization. The effects of melatonin (1 µM) on prolonged microglial exposure to Aß42 were analyzed for their protective potential. Melatonin was able to prolong SIRT1 and BDNF upregulation, as well as to prevent NF-kB nuclear translocation and acetylation. These effects were sensitive to the melatonin receptor antagonist, luzindole (25 µM). In conclusion, our data define an early microglial defensive response to Aß42, featuring SIRT1-mediated BDNF upregulation that can be exogenously modulated by melatonin, thus identifying an important target for neuroprotection.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Prognostic_studies
Language:
En
Journal:
Biomedicines
Year:
2021
Document type:
Article
Affiliation country: