Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease

Progressive cerebral deposition of amyloid-beta (A beta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inf lammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease-implicated pr oteins can induce antigen-specific anti-inflammatory immune responses in mu cosal lymphoid tissue which then act systemically. We hypothesized that chr onic mucosal administration of A beta peptide might induce an anti-inflamma tory process in AD brain tissue that could beneficially affect the neuropat hological findings. To test this hypothesis, we treated PDAPP mice, a trans genic line displaying numerous neuropathological features of AD, between th e ages of similar to 5 and similar to 12 months with human A beta synthetic peptide mucosally each week. We found significant decreases in the cerebra l A beta plaque burden and A beta 42 levels in mice treated intranasally wi th A beta peptide versus controls treated with myelin basic protein or left untreated. This lower A beta burden was associated with decreased local mi croglial and astrocytic activation, decreased neuritic dystrophy, serum ant i-A beta antibodies of the IgG1 and IgG2b classes, and mononuclear cells in the brain expressing the anti-inflammatory cytokines interleukin-4, interl eukin-10, and tumor growth factor-beta. Our results demonstrate that chroni c nasal administration of A beta peptide can induce an immune response to A beta that decreases cerebral A beta deposition, suggesting a novel mucosal immunological approach for the treatment and prevention of AD.