Naringenin promotes microglial M2 polarization and Aβ degradation enzyme expression

Abstract

Two kinds of microglia are known, classical M1 and alternative M2 phenotypes. Amyloid β (Aβ), a critical cause of Alzheimer's disease (AD), promotes M1 microglial polarization, leading to neuroinflammation and neuronal death. M2 microglia play important roles in anti-inflammatory effects, Aβ clearance, and memory recovery in AD. Therefore, increasing of M2 microglia is expected to recover from AD. We previously found that naringenin, a blood-brain barrier penetrating compound, decreased Aβ deposits and recovers memory function in transgenic AD model mice. Naringenin reportedly showed anti-inflammatory properties. Here, we aim to investigate potential effects of naringenin on microglial polarization and to reveal the underlying mechanisms of Aβ reduction. Primary cultured cortical microglia were treated with Aβ 1-42 , following administration of naringenin. Naringenin remarkably promoted M2 microglia polarization and inhibited Aβ 1-42 -induced M1 microglia activation. Because microglia reportedly played a critical role in cerebral Aβ clearance through Aβ degradation enzymes after phagocytosis, we investigated the expression of Aβ degradation enzymes, such as neprilysin and insulin degradation enzyme. After naringenin treatment, these Aβ degradation enzymes were downregulated in M1 microglia and upregulated in M2 microglia. Taken together, our results showed that naringenin increased Aβ degradation enzymes in M2 microglia, probably leading to Aβ plaque reduction.

Hederagenin Modulates M1 Microglial Inflammatory Responses and Neurite Outgrowth

“…Nge was used as a positive control, as in our previous report. 7 The levels of IL-1β, TNF-α, and IL-6 were significantly increased, whereas those of IL-10 were decreased compared with the levels in the control group after LPS treatment. IL-1β, TNF-α, and IL-6 productions were significantly inhibited after the 12-hour pretreatment with either 1 and 10 µM HED or Nge (Figure 3(C)-(E)).…”

“…18 Moreover, M1 microglia express specific proteins, including CD16/32 and iNOS, and M2 microglia express Arginase I, CD206, and Ym1. 7 To confirm whether HED affects microglial polarization, 1 and 10 µM HED were used to pretreat primary microglia for 2 hours followed by treatment with 100 ng/mL LPS for another 24 hours (Figure 4(A)). The analysis results showed that CD206 expression was significantly downregulated, while that of iNOS was upregulated after LPS treatment (Figure 4(B) and (C)).…”

“…Primary microglia were obtained from mice cortices as previously reported, with minor modifications. 7,26 Briefly, we dissected the cerebral cortices from ICR mice at postnatal days 2 to 4. The cortices were minced after removing the dura mater and digested with 0.25% trypsin-EDTA at 37 °C for 30 minutes.…”

“…5 Polarization of microglia to the M1 phenotype is accompanied by disease progression. 6,7 Thus, the inhibition of M1 microglial polarization contributes to the amelioration of the neuroinflammatory microenvironment in the brain in AD.…”

“…We have recently reported that naringenin (Nge) is a useful M1 microglia inhibitor for the treatment of AD. 7 In our ongoing screening of naturally occurring anti-inflammatory compounds, hederagenin (HED; Figure 1) exhibited a potent anti-neuroinflammatory effect in LPS-stimulated microglia. HED has been reported to possess diverse bioactivities, such as the inhibition of leishmania, tumors, acute edematous inflammation, and LPS-induced NO production in macrophages.…”