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

Akihiro Mouri^*,1, Yukihiro Noda^*,,1, Hideo Hara^*,,1, Hiroyuki Mizoguchi^*, Takeshi Tabira and Toshitaka Nabeshima^*,2

^* Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan;

Division of Clinical Science and Neuropsychopharmacology in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, Japan; and

Department of Vascular Dementia Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Morioka, Obu, Japan

²Correspondence: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan. E-mail: tnabeshi{at}med.nagoya-u.ac.jp

Immunotherapy with Aß 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 Aß cDNA (AAV/Aß). The vaccine reduces the amount of Aß 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/Aß to Tg2576 mice at the age of 10 months alleviated progressive cognitive impairment with decreased Aß deposition, insoluble Aß, soluble Aß oligomer (Aß*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/Aß-vaccinated Tg2576 mice at 13 months of age. Taken together, these results suggest that immunotherapy with AAV/Aß is a safe and effective treatment for AD.—Mouri, A., Noda, Y., Hara, H., Mizoguchi, H., Tabira, T., Nabeshima, T. Oral vaccination with a viral vector containing Aß cDNA attenuates age-related Aß accumulation and memory deficits without causing inflammation in a mouse Alzheimer model.

Key Words: Aß-peptide • cognitive dysfunction