Background: Neuroinflammation plays an important role in the pathophysiological process
of various neurodegenerative diseases. It is well known that curcumin has obvious anti-inflammatory
effects in various neuroinflammation models. However, its effect on the modulation of microglial polarization
is largely unknown.
Objective: This study aimed to investigate whether curcumin changed microglia to an anti-inflammatory
M2-phenotype by activating the AMP-activated protein kinase (AMPK) signaling pathway.
Methods: LPS treatment was used to establish BV2 cells and primary microglia neuroinflammation
models. The neuroinflammation mouse model was established by an intracerebroventricular (ICV) injection
of lipopolysaccharide (LPS) in the lateral septal complex region of the brain. TNF-α was measured
by ELISA, and cell viability was measured by Cell Counting Kit-8 (CCK-8). The expression of proinflammatory
and anti-inflammatory cytokines was examined by Q-PCR and Western blot analysis.
Phenotypic polarization of BV2 microglia was detected by immunofluorescence.
Results: Curcumin enhanced AMPK activation in BV2 microglial cells in the presence and absence of
LPS. Upon LPS stimulation, the addition of curcumin promoted M2 polarization of BV2 cells, as evidenced
by suppressed M1 and the elevated M2 signature protein and gene expression. The effects of
curcumin were inhibited by an AMPK inhibitor or AMPK knockdown. Calmodulin-dependent protein
kinase kinase β (CaMKKβ) and liver kinase B1 (LKB1) are upstream kinases that activate AMPK. Curcumin
can activate AMPK in Hela cells, which do not express LKB1. However, both the CaMKKβ inhibitor
and siRNA blocked curcumin activation of AMPK in LPS-stimulated BV2 cells. Moreover, the
CaMKKβ inhibitor and siRNA weaken the effect of curcumin suppression on M1 and enhancement of
M2 protein and gene expression in LPS-stimulated BV2 cells. Finally, curcumin enhanced AMPK activation
in the brain area where microglia were over-activated upon LPS stimulation in an in vivo neuroinflammation
model. Moreover, curcumin also suppressed M1 and promoted M2 signature protein and
gene expression in this in vivo model.
Conclusion: Curcumin enhances microglia M2 polarization via the CaMKKβ-dependent AMPK signaling
pathway. Additionally, curcumin treatment was found to be neuroprotective and thus might be considered
as a novel therapeutic agent to treat the neurodegenerative disease such as Alzheimer‘s disease,
Parkinson's disease, etc.