Nonviral DNA Vaccination Augments Microglial Phagocytosis of β-Amyloid Deposits as a Major Clearance Pathway in an Alzheimer Disease Mouse Model

Abstract

Immunotherapies markedly reduce beta-amyloid (Abeta) burden and reverse behavioral impairment in mouse models of Alzheimer disease. We previously showed that new Abeta DNA vaccines reduced Abeta deposits in Alzheimer disease model mice without detectable side effects. Although they are effective, the mechanisms of Abeta reduction by the DNA vaccines remain to be elucidated. Here, we analyzed vaccinated and control Alzheimer disease model mice from 4 months to 15 months of age to assess which of several proposed mechanisms may underlie the beneficial effects of this vaccination. Immunohistochemical analysis revealed that activated microglial numbers increased significantly in the brains of vaccinated mice after DNA vaccination both around Abeta plaques and in areas remote from them. Microglia in treated mice phagocytosed Abeta debris more frequently than they did in untreated mice. Although microglia had an activated morphological phenotype, they did not produce significant amounts of tumor necrosis factor. Amyloid plaque immunoreactivity and Abeta concentrations in plasma increased slightly in vaccinated mice compared with controls at 9 but not at 15 months of age. Collectively, these data suggest that phagocytosis of Abeta deposits by microglia plays a central role in Abeta reduction after DNA vaccination.