Chronic hyperglycemia regulates microglia polarization through ERK5.

Area of Science:

• Neuroscience
• Immunology
• Endocrinology

Background:

• Diabetic patients have increased risk for Alzheimer's disease (AD), with microglia playing a key role.
• The impact of high glucose (HG) on microglia and the involvement of extracellular-signal-regulated kinase 5 (ERK5) signaling remain unclear.

Purpose of the Study:

• To investigate the effects of HG on microglial polarization.
• To determine the role of ERK5 signaling in HG-induced microglial changes and their impact on neuronal health.

Main Methods:

• Microglia cultured in high glucose (HG) versus normal glucose (NG) conditions.
• Assessment of microglial phenotype (M2a, M2b, M1) and ERK5 activation.
• Pharmacological inhibition (BIX021895) and genetic manipulation (MEK5DD) of ERK5 signaling.
• Analysis of conditioned media's effect on neuronal apoptosis.

Main Results:

• HG initially induced M2a microglial differentiation with ERK5 activation.
• Prolonged HG exposure led to M2b and M1 polarization, with decreased ERK5 activation.
• ERK5 inhibition promoted M2b/M1 polarization, while sustained ERK5 activation maintained the M2a phenotype.
• M2a microglia protected neurons, whereas M2b/M1 microglia exacerbated neuronal apoptosis.

Conclusions:

• Chronic hyperglycemia drives microglial polarization towards a pro-inflammatory M1-like state.
• Sustained ERK5 signaling activation can counteract this detrimental shift, offering a potential therapeutic target for diabetic AD patients.