Key Aging-Associated Alterations in Primary Microglia Response to Beta-Amyloid Stimulation
Cláudia Caldeira1, Carolina Cunha1, Ana R Vaz1,2
1Neuron Glia Biology in Health and Disease, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de LisboaLisbon, Portugal.
Frontiers in Aging Neuroscience
|September 16, 2017
Summary
Microglia aged in vitro show reduced reactivity to amyloid-beta (Aβ) in Alzheimer's disease (AD). Older microglia exhibit decreased phagocytosis and inflammatory responses, suggesting different therapeutic strategies for early versus late AD stages.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Alzheimer's disease (AD) pathogenesis involves amyloid-beta (Aβ) aggregation and microglia-mediated inflammation.
- Microglia exhibit diverse phenotypes throughout AD progression, and their exact role remains under investigation.
- Excessive Aβ production can disrupt normal microglial cell function.
Purpose of the Study:
- To investigate differential microglial responses to Aβ based on in vitro aging.
- To compare the reactivity of microglia cultured for 2 days versus 16 days in vitro (DIV) when exposed to Aβ.
Main Methods:
- Primary microglia were cultured for 2 DIV and 16 DIV.
- Cells were treated with 1000 nM Aβ1-42 for 24 hours.
- Assessed cell viability, morphometric changes, phagocytosis, migration, autophagy, inflammatory mediator expression, receptor levels, senescence markers, and miRNA expression.
Main Results:
- 16 DIV microglia showed less pronounced morphometric activation, reduced phagocytosis, migration, and autophagy compared to 2 DIV microglia after Aβ treatment.
- 16 DIV cells exhibited increased CD33 and senescence markers (SA-β-gal, miR-146a), with reduced TREM2 and MFG-E8 levels.
- 2 DIV microglia showed prominent inflammatory mediator activation (HMGB1, cytokines, TLR2, TLR4, CX3CR1), while 16 DIV cells showed increased MMP9; both showed mixed M1/M2 markers.
Conclusions:
- Microglia display age-associated changes in reactivity to Aβ in vitro, with a decline in function from 2 DIV to 16 DIV.
- Reduced phagocytosis and inflammatory responses in aged microglia correlate with altered receptor expression and miRNA profiles.
- Findings suggest that therapeutic interventions for AD may need to be tailored to the stage of the disease due to heterogeneous microglial responses.
