Oral vaccination with a viral vector containing Abeta cDNA attenuates age-related Abeta accumulation and memory deficits without causing inflammation in a mouse Alzheimer model

• Published in: The FASEB journal 2007-07, Vol.21 (9), p.2135-2148
• Main Authors: Mouri, Akihiro, Noda, Yukihiro, Hara, Hideo, Mizoguchi, Hiroyuki, Tabira, Takeshi, Nabeshima, Toshitaka
• Format: Article
• Language: English
• Subjects: Administration, Oral; Alzheimer Disease - psychology; Alzheimer Disease - therapy; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - immunology; Animals; Association Learning; Avoidance Learning; Brain - immunology; Brain - pathology; Brain Chemistry; Dependovirus - genetics; Disease Models, Animal; DNA, Complementary - genetics; DNA, Complementary - immunology; DNA, Complementary - therapeutic use; Drug Evaluation, Preclinical; Exploratory Behavior; Fear; Female; Freezing Reaction, Cataleptic; Genetic Vectors - immunology; Genetic Vectors - therapeutic use; Immunotherapy, Active; Maze Learning; Mice; Mice, Transgenic; Microglia - pathology; Motor Activity; Mutation, Missense; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - immunology; Plaque, Amyloid; Point Mutation; Recognition (Psychology); Solubility; Synapses - pathology; Vaccination; Vaccines, DNA - immunology; Vaccines, DNA - therapeutic use
• ISSN: 1530-6860

Immunotherapy with Abeta is expected to bring great improvement for Alzheimer disease (AD). However, clinical trials have been suspended because of meningoencephalitics, which accompanied lymphocytic infiltration. We have developed an oral vaccine for AD with a recombinant adeno-associated viral vector carrying Abeta cDNA (AAV/Abeta). The vaccine reduces the amount of Abeta deposited without lymphocytic infiltration in APP transgenic (Tg2576) mice. In the present study, Tg2576 mice showed progressive cognitive impairments in the novel object recognition test, Y-maze test, water maze test, and contextual conditioned fear learning test. A single oral administration of AAV/Abeta to Tg2576 mice at the age of 10 months alleviated progressive cognitive impairment with decreased Abeta deposition, insoluble Abeta, soluble Abeta oligomer (Abeta*56), microglial attraction, and synaptic degeneration induced in the brain regions at the age of 13 months. A histological analysis with hematoxylin and eosin and an immunohistochemical analysis with antibodies against CD3, CD4, CD8, and CD19 suggested there was no lymphocytic infiltration or microhemorrhage in the brain of AAV/Abeta-vaccinated Tg2576 mice at 13 months of age. Taken together, these results suggest that immunotherapy with AAV/Abeta is a safe and effective treatment for AD.