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 β-amyloid peptide 1-42 (Aβ42; 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 Aβ42-induced increase of SIRT1 expression, nuclear localization, and activity. SIRT1 modulation involved adenosine monophosphate-regulated kinase (AMPK), which was promptly (30 min) phosphorylated by Aβ42, while the AMPK inhibitor BML-275 (2 μM) attenuated Aβ42-induced SIRT1 increase. Initially observed microglial responses appeared transient, as microglial features changed when exposure to Aβ42 was prolonged (0.2 μM for 72 h). While SIRT1 and BDNF levels were reduced, the expression of inflammatory markers IL-1β 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 Aβ42 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 Aβ42, featuring SIRT1-mediated BDNF upregulation that can be exogenously modulated by melatonin, thus identifying an important target for neuroprotection.
Highlights
Amyloid β peptide 1-42 (Aβ42) was initially analyzed at the mRNA level by Quantitative real-time PCR (qRT-PCR)
After 6 h of exposure to Aβ42 alone, the population of nuclear SIRT1positive cells was increased by 108% over the control (Figure 5D)
We focused on NF-kB, a well-known target of Silent Information Regulator homolog 1 (SIRT1), with a crucial role in miWe focused on NF-kB, a well-known target
Summary
A salient feature of AD is that it develops slowly over the years, remaining asymptomatic for up to two decades before diagnosis is possible [1,2]. By this time, neurodegeneration is so advanced that chances for treatment are reduced, accounting at least in part for current failure to develop effective disease-modifying therapies [1,3]. From a molecular point of view, hallmarks of AD are the increased brain levels of the beta amyloid peptide (Aβ) and phosphorylated tau protein, which respectively aggregate into extracellular plaques and intracellular tangles [4,5,6,7].
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