Transition from an M1 to a mixed neuroinflammatory phenotype increases amyloid deposition in APP/PS1 transgenic mice

Background: The polarization to different neuroinflammatory phenotypes has been described in early Alzheimer's disease, yet the impact of these phenotypes on amyloid-beta (A beta) pathology remains unknown. Short-term studies show that induction of an M1 neuroinflammatory phenotype reduces A beta, 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 IFN gamma or green fluorescent protein in the frontal cortex and hippocampus. Mice were sacrificed 4 or 6 months post-injection. ELISA measurements were used for IFN gamma protein levels and biochemical levels of A beta. The neuroinflammatory phenotype was determined through quantitative PCR. Microglia, astrocytes, and A beta levels were assessed with immunohistochemistry. Results: AAV expressing IFN gamma induced an M1 neuroinflammatory phenotype at 4 months and a mixed phenotype along with an increase in A beta 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 IFN gamma.. Conclusions: Expression of IFN gamma 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.