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Transition from an M1 to a mixed neuroinflammatory phenotype increases amyloid deposition in APP/PS1 transgenic mice
Erica M Weekman, Tiffany L Sudduth, Erin L Abner
1Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA. donna.wilcock@uky.edu.
Background:
The polarization to different neuroinflammatory phenotypes has been described in early Alzheimer's disease, yet the impact of these phenotypes on amyloid-beta (Aβ) pathology remains unknown. Short-term studies show that induction of an M1 neuroinflammatory phenotype reduces Aβ, but long-term studies have not been performed that track the neuroinflammatory phenotype.
Methods:
Wild-type and APP/PS1 transgenic mice aged 3 to 4 months received a bilateral intracranial injection of adeno-associated viral (AAV) vectors expressing IFNγ or green fluorescent protein in the frontal cortex and hippocampus. Mice were sacrificed 4 or 6 months post-injection. ELISA measurements were used for IFNγ protein levels and biochemical levels of Aβ. The neuroinflammatory phenotype was determined through quantitative PCR. Microglia, astrocytes, and Aβ levels were assessed with immunohistochemistry.
Results:
AAV expressing IFNγ induced an M1 neuroinflammatory phenotype at 4 months and a mixed phenotype along with an increase in Aβ at 6 months. Microglial staining was increased at 6 months and astrocyte staining was decreased at 4 and 6 months in mice receiving AAV expressing IFNγ.
Conclusions:
Expression of IFNγ through AAV successfully induced an M1 phenotype at 4 months that transitioned to a mixed phenotype by 6 months. This transition also appeared with an increase in amyloid burden suggesting that a mixed phenotype, or enhanced expression of M2a and M2c markers, could contribute to increasing amyloid burden and disease progression.
Insights
Inducing an M1 neuroinflammatory phenotype in mice initially reduced amyloid-beta (Aβ) but later transitioned to a mixed phenotype, increasing Aβ burden and disease progression.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Neuroinflammation plays a role in Alzheimer's disease (AD).
- The long-term impact of specific neuroinflammatory phenotypes on amyloid-beta (Aβ) pathology is not well understood.
- Previous short-term studies suggest M1 neuroinflammation may reduce Aβ.
Purpose of the Study:
- To investigate the long-term effects of an M1 neuroinflammatory phenotype on Aβ pathology in a mouse model of AD.
- To track the transition of neuroinflammatory phenotypes over time and their correlation with Aβ accumulation.
Main Methods:
- Adeno-associated viral (AAV) vectors expressing Interferon-gamma (IFNγ) were used to induce neuroinflammation in APP/PS1 transgenic mice.
- Mice were analyzed 4 and 6 months post-injection for IFNγ levels, Aβ burden, and neuroinflammatory markers (microglia, astrocytes).
- Quantitative PCR and immunohistochemistry were employed to assess neuroinflammatory phenotypes and cellular changes.
Main Results:
- IFNγ induction led to an M1 neuroinflammatory phenotype at 4 months, which shifted to a mixed phenotype by 6 months.
- A significant increase in Aβ levels was observed at 6 months post-IFNγ induction.
- Microglial staining increased, while astrocyte staining decreased at 4 and 6 months in the IFNγ-treated group.
Conclusions:
- IFNγ-induced M1 phenotype transitions to a mixed phenotype over 6 months in AD mouse models.
- This phenotypic shift correlates with increased amyloid burden, suggesting a role for mixed or M2-like phenotypes in AD progression.
- The findings highlight the dynamic nature of neuroinflammation and its complex relationship with amyloid pathology in Alzheimer's disease.
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