Diminished Amyloid-β Burden in Tg2576 Mice Following a Prophylactic Oral Immunization with a Salmonella-Based Amyloid-β Derivative Vaccine

Article type: Research Article

Authors: Boutajangout, Allal^{a; b;} | Goni, Fernando^{c; e;} | Knudsen, Elin^b | Schreiber, Fernanda^f | Asuni, Ayodeji^b | Quartermain, David^c | Frangione, Blas^{b; d} | Chabalgoity, Alejandro^f | Wisniewski, Thomas^{b; c; d} | Sigurdsson, Einar M.^{a; b; *}

Affiliations: [a] Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY, USA | [b] Department of Psychiatry, New York University School of Medicine, New York, NY, USA | [c] Department of Neurology, New York University School of Medicine, New York, NY, USA | [d] Department of Pathology, New York University School of Medicine, New York, NY, USA | [e] Department of Immunology, School of Chemistry, University of Uruguay, Montevideo, Uruguay | [f] Department of Biotechnology, School of Medicine, University of Uruguay, Montevideo, Uruguay

Correspondence: [*] Corresponding author: Einar M. Sigurdsson, Ph.D., New York University, School of Medicine, Depts. Of Physiology and Neuroscience, and Psychiatry, Medical Science Building, MSB459, 550 First Avenue, New York, NY 10016, USA. Tel.: +1 212 263 3913; Fax: +1 212 263 2160; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. Prior to the side effects in the first Elan/Wyeth AD vaccine trial, we proposed using amyloid-β (Aβ) derivatives as a safer approach. The route of administration may also affect vaccine safety. To assess the feasibility of oral immunization that promotes mucosal immunity, Tg2576 AD model mice were treated prophylactically three times over 6 weeks starting at 3–5 months of age with a Salmonella vaccine expressing K6Aβ1-30. At 22–24 months of age, cortical Aβ plaque burden and total Aβ40/42 levels were reduced by 48–75% in the immunized mice compared to controls, which received unmodified Salmonella. Plaque clearance was not associated with increased microglial activation, which may be explained by the long treatment period. Furthermore, cerebral microhemorrhages were not increased in the treated mice in contrast to several passive Aβ antibody studies. These results further support our findings with this immunogen delivered subcutaneously and demonstrate its efficacy when given orally, which may provide added benefits for human use.

Keywords: Amyloid-β, immunization, microhemorrhages, oral, salmonella, transgenic mice, vaccine

DOI: 10.3233/JAD-2009-1204

Journal: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 961-972, 2009