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The Journal of Neuroscience, November 14, 2007, 27(46):12721-12731; doi:10.1523/JNEUROSCI.3201-07.2007

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Neurobiology of Disease
Alzheimer's Disease Peptide Epitope Vaccine Reduces Insoluble But Not Soluble/Oligomeric Aß Species in Amyloid Precursor Protein Transgenic Mice

Irina Petrushina,^1 * Anahit Ghochikyan,^3 * Mikayel Mktrichyan,³ Gregory Mamikonyan,³ Nina Movsesyan,¹ Hayk Davtyan,³ Archita Patel,¹ Elizabeth Head,^1,2 David H. Cribbs,^1,2  and Michael G. Agadjanyan^1,3 

¹The Institute for Brain Aging and Dementia and ²Department of Neurology, University of California, Irvine, Irvine, California 92697-4540, and ³The Institute for Molecular Medicine, Department of Immunology, Huntington Beach, California 92647

Correspondence should be addressed to Dr. Michael G. Agadjanyan, The Institute for Molecular Medicine, 16371 Gothard Street, H, Huntington Beach, CA 92647-3652. Email: magadjanyan{at}immed.org

Active vaccination of elderly Alzheimer's disease (AD) patients with fibrillar amyloid-ß peptide (Aß₄₂), even in the presence of a potent Th1 adjuvant, induced generally low titers of antibodies in a small fraction (20% responders) of those that received the AN-1792 vaccine. To improve the immunogenicity and reduce the likelihood of inducing adverse autoreactive T-cells specific for Aß₄₂, we previously tested in wild-type mice an alternative approach for active immunization: an epitope vaccine that selectively initiate B cell responses toward an immunogenic self-epitope of Aß in the absence of anti-Aß T cell responses. Here, we describe a second generation epitope vaccine composed of two copies of Aß_1–11 fused with the promiscuous nonself T cell epitope, PADRE (pan human leukocyte antigen DR-binding peptide) that completely eliminates the autoreactive T cell responses and induces humoral immune responses in amyloid precursor protein transgenic 2576 mice with pre-existing AD-like pathology. Based on the titers of anti-Aß_1–11 antibody experimental mice were divided into low, moderate and high responders, and for the first time we report a positive correlation between the concentration of anti-Aß_1–11 antibody and a reduction of insoluble, cerebral Aß plaques. The reduction of insoluble Aß deposition was not associated with adverse events, such as CNS T cell or macrophage infiltration or microhemorrhages. Surprisingly, vaccination did not alter the levels of soluble Aß. Alternatively, early protective immunization before substantial neuropathology, neuronal loss and cognitive deficits have become firmly established may be more beneficial and safer for potential patients, especially if they can be identified in a preclinical stage by the development of antecedent biomarkers of AD.

Key words: immunotherapy; Alzheimer's disease; epitope vaccine; antibody; PADRE; ß-amyloid

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Received July 13, 2007; revised Oct. 1, 2007; accepted Oct. 7, 2007.

Correspondence should be addressed to Dr. Michael G. Agadjanyan, The Institute for Molecular Medicine, 16371 Gothard Street, H, Huntington Beach, CA 92647-3652. Email: magadjanyan{at}immed.org

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