Amyloid accumulation1 and accompanying inflammation—including both the activation of glial cells2 and the accrual of inflammatory proteins, such as complement, 3, 4 cytokines, 5 and acute phase proteins6–8—play key roles in the pathogenesis of Alzheimer’s disease (AD). 9 Mucosal administration of proteins implicated in a disease can decrease organ-specific inflammatory processes in a number of animal models of autoimmune disorders, including those affecting the nervous system, principally by inducing antiinflammatory IL-4/IL-10 (Th2) and TGFβ immune responses in mucosal lymphoid tissue that then act systemically. 10 For example, oral or nasal administration of myelin basic protein (MBP) 11–13 or the acetylcholine receptor14, 15 can suppress experimental autoimmune encephalomyelitis (EAE) and experimental myasthenia gravis, respectively.

In an effort to reduce the inflammation associated with Aβ deposition via mucosal tolerance, we tested the effects of nasal or oral administration of Aβ1–40 peptide and a control protein, myelin basic protein (MBP), by treating 52 PD-APP transgenic mice, an animal model with certain key features of AD, 16–18 on a weekly basis for seven months (ages 5 to 12 months). Doses were chosen based on preliminary nasal and oral studies in nontransgenic mice. Treatment groups included (1) untreated (n= 7);(2) MBP oral, 500 µg (n= 5);(3) MBP nasal, 50 µg (n= 6);(4) Aβ oral, 10 µg (n= 9);(5) Aβ oral, 100 µg (n= 9);(6) Aβ nasal, 5 µg (n= 7); and (7) Aβ nasal, 25 µg (n= 9). During the first week, mice were fed five times or nasally treated three times on consecutive days. Thereafter, mice were fed or nasally treated each week for seven months and then sacrificed. The brain from each mouse was removed and divided in half along the sagittal midline. One hemisphere was formalin fixed and embedded in paraffin for immunohistochemical analysis. Of the contralateral hemispheres, half were snap frozen for biochemical analysis; the other half were embedded sagittally in OCT and snap frozen for cryosectioning and immunohistochemistry.