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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Serum amyloid a differentially activates microglia and astrocytes via the PI3K pathway
1School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P.R. China.
Abstract:
Microglia and astrocytes in the brain play an important role in the development and progression of Alzheimer's disease (AD). Serum amyloid A (SAA) is a major acute-phase protein produced locally in the brain and colocalizes with senile plaques in AD patients. We investigated whether SAA plays a role in the development of AD. The viability of cultured primary microglia and astrocytes was measured by MTT; cell cycle and apoptosis analysis was also conducted. Cultured microglia and astrocytes were stimulated with 1 μM SAA for different periods of time (2, 4, 6, 12 h) or treated with 1 μM SAA with or without 15 min pretreatment of MAPK or PI3K inhibitors. Total RNA was extracted for qPCR analysis. SAA induced morphological changes of primary microglia but not astrocytes. Interestingly, SAA increased the viability of microglia by inhibiting their apoptosis and reduced the viability of astrocytes by inducing G1 cell cycle arresting. SAA treatment increased the mRNA levels of IL-6, TNF-α, IL12p40, IL23p19, and IL-10, with higher potency in microglia than in astrocytes. However, SAA induced more iNOS mRNA in astrocytes than in microglia. SAA induced these cytokines and iNOS expression by activating the PI3K pathway in both glial cells, but selectively activated the JNK pathway in microglia and the NF-κB pathway in astrocytes. These results suggest that SAA can stimulate a different reactive phenotype in microglia and astrocytes, and SAA regulates cell viability differently in these two glial cells in part through the PI3K pathway.
Insights
Serum amyloid A (SAA) differentially affects brain immune cells in Alzheimer's disease (AD) models. SAA impacts microglia and astrocyte viability and inflammatory responses, suggesting a role in AD pathogenesis.
Area of Science:
- Neuroimmunology
- Molecular Biology
- Alzheimer's Disease Research
Background:
- Microglia and astrocytes are key players in Alzheimer's disease (AD) pathogenesis.
- Serum amyloid A (SAA), an acute-phase protein, is found in AD senile plaques.
- The specific role of SAA in glial cell responses in AD remains unclear.
Purpose of the Study:
- To investigate the role of Serum amyloid A (SAA) in the development of Alzheimer's disease (AD).
- To examine SAA's effects on microglia and astrocyte viability, cell cycle, apoptosis, and inflammatory gene expression.
- To elucidate the signaling pathways involved in SAA-mediated glial cell responses.
Main Methods:
- Primary microglia and astrocytes were cultured and treated with SAA.
- Cell viability, cell cycle, and apoptosis were assessed using MTT assays and flow cytometry.
- mRNA levels of inflammatory cytokines and iNOS were quantified via qPCR after SAA stimulation with or without pathway inhibitors (MAPK, PI3K).
Main Results:
- SAA induced morphological changes in microglia but not astrocytes.
- SAA increased microglia viability by inhibiting apoptosis, while reducing astrocyte viability via G1 cell cycle arrest.
- SAA upregulated pro-inflammatory cytokines (IL-6, TNF-α, IL12p40, IL23p19, IL-10) and iNOS, with differential potency between microglia and astrocytes.
- SAA activated the PI3K pathway in both cell types, additionally activating JNK in microglia and NF-κB in astrocytes.
Conclusions:
- SAA differentially modulates microglia and astrocyte phenotypes and inflammatory responses.
- SAA influences glial cell viability through distinct mechanisms, impacting apoptosis and cell cycle.
- SAA's distinct effects on glial cells, mediated by specific signaling pathways, suggest a complex role in Alzheimer's disease progression.
