Related Experiment Video
Updated: Jul 19, 2026
Reprograming Model of Human Monocyte-derived Macrophages for In-vitro Assays
Published on: April 18, 2025
Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD
Carol A Colton1, Ryan T Mott, Hayley Sharpe
1Duke University Medical Center, Division of Neurology, Durham, NC 27710, USA. glia01@aol.com
Background:
Microglia are associated with neuritic plaques in Alzheimer disease (AD) and serve as a primary component of the innate immune response in the brain. Neuritic plaques are fibrous deposits composed of the amyloid beta-peptide fragments (Abeta) of the amyloid precursor protein (APP). Numerous studies have shown that the immune cells in the vicinity of amyloid deposits in AD express mRNA and proteins for pro-inflammatory cytokines, leading to the hypothesis that microglia demonstrate classical (Th-1) immune activation in AD. Nonetheless, the complex role of microglial activation has yet to be fully explored since recent studies show that peripheral macrophages enter an "alternative" activation state.
Methods:
To study alternative activation of microglia, we used quantitative RT-PCR to identify genes associated with alternative activation in microglia, including arginase I (AGI), mannose receptor (MRC1), found in inflammatory zone 1 (FIZZ1), and chitinase 3-like 3 (YM1).
Results:
Our findings confirmed that treatment of microglia with anti-inflammatory cytokines such as IL-4 and IL-13 induces a gene profile typical of alternative activation similar to that previously observed in peripheral macrophages. We then used this gene expression profile to examine two mouse models of AD, the APPsw (Tg-2576) and Tg-SwDI, models for amyloid deposition and for cerebral amyloid angiopathy (CAA) respectively. AGI, MRC1 and YM1 mRNA levels were significantly increased in the Tg-2576 mouse brains compared to age-matched controls while TNFalpha and NOS2 mRNA levels, genes commonly associated with classical activation, increased or did not change, respectively. Only TNFalpha mRNA increased in the Tg-SwDI mouse brain. Alternative activation genes were also identified in brain samples from individuals with AD and were compared to age-matched control individuals. In AD brain, mRNAs for TNFalpha, AGI, MRC1 and the chitinase-3 like 1 and 2 genes (CHI3L1; CHI3L2) were significantly increased while NOS2 and IL-1beta mRNAs were unchanged.
Conclusion:
Immune cells within the brain display gene profiles that suggest heterogeneous, functional phenotypes that range from a pro-inflammatory, classical activation state to an alternative activation state involved in repair and extracellular matrix remodeling. Our data suggest that innate immune cells in AD may exhibit a hybrid activation state that includes characteristics of classical and alternative activation.
Insights
Microglia in Alzheimer disease (AD) show a mixed activation state, not just pro-inflammatory. This suggests a complex immune response involving both classical and alternative activation pathways, impacting brain repair and remodeling.
Area of Science:
- Neuroimmunology
- Alzheimer's Disease Research
- Innate Immune Response
Background:
- Microglia, the brain's immune cells, are implicated in Alzheimer disease (AD) pathogenesis, particularly around amyloid plaques.
- Traditionally, microglia in AD were thought to exhibit classical (pro-inflammatory) activation.
- Emerging evidence suggests peripheral macrophages can adopt an 'alternative' activation state, prompting investigation into microglial phenotypes.
Purpose of the Study:
- To investigate the potential for alternative activation in microglia.
- To characterize microglial gene expression profiles in mouse models of AD and human AD brain samples.
Main Methods:
- Quantitative RT-PCR was used to identify genes associated with alternative microglial activation, including arginase I (AGI), mannose receptor (MRC1), FIZZ1, and YM1.
- Gene expression was analyzed in two mouse models of AD (APPsw and Tg-SwDI) and in human AD brain tissue.
Main Results:
- Microglia treated with IL-4 and IL-13 exhibited an alternative activation gene profile.
- In Tg-2576 AD mouse models, mRNA levels for alternative activation genes (AGI, MRC1, YM1) were elevated, while classical activation markers (TNFalpha, NOS2) showed varied changes.
- Human AD brains displayed increased mRNA for alternative activation markers (AGI, MRC1, CHI3L1, CHI3L2) alongside TNFalpha, suggesting a hybrid activation state.
Conclusions:
- Brain immune cells, including microglia, exhibit diverse functional phenotypes.
- The findings suggest that microglia in AD may not solely be pro-inflammatory but possess a hybrid activation state with both classical and alternative characteristics.
- This hybrid state could influence brain repair and extracellular matrix remodeling in AD.
