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The Journal of Neuroscience, July 14, 2004, 24(28):6277-6282; doi:10.1523/JNEUROSCI.1344-04.2004
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Neurobiology of Disease
An Attenuated Immune Response Is Sufficient to Enhance Cognition in an Alzheimer's Disease Mouse Model Immunized with Amyloid- Derivatives
Einar M. Sigurdsson,1,2
Elin Knudsen,1
Ayodeji Asuni,1
Cheryl Fitzer-Attas,4
Daniel Sage,1
David Quartermain,3
Fernando Goni,1,5
Blas Frangione,1,2 and
Thomas Wisniewski1,2,3
Departments of 1Psychiatry, 2Pathology, and 3Neurology, New York University School of Medicine, New York, New York 10016, 4Mindset BioPharmaceuticals, Jerusalem 91450, Israel, and 5Department of Immunology, University of Uruguay, Montevideo CP11600, Uruguay
Immunization with amyloid- (A) 1-42 has been shown to reduce amyloid burden and improve cognition in Alzheimer's disease (AD) model mice. In a human trial, possible cognitive benefit was found but in association with significant toxicity in a minority of patients. We proposed that immunization with nonfibrillogenic A derivatives is much less likely to produce toxicity and have previously shown that one such derivative (K6A1-30) can reduce amyloid burden in mice to a similar extent as A1-42. Here, we immunized AD model mice (Tg2576) with A1-30[E18E19] or with K6A1-30[E18E19]. These peptides were designed to be nontoxic and to produce less T-cell response, which has been linked to toxicity. K6A1-30[E18E19] induced primarily an IgM response, whereas A1-30[E18E19] induced an IgG titer that was lower than previously seen with K6A1-30 or A1-42. However, both treated animal groups performed better than Tg controls in the radial arm maze. Amyloid burden was similar in A1-30[E18E19]-vaccinated mice and their Tg controls, whereas the number of medium and small sized plaques was reduced (29-34%) in K6A1-30[E18E19]-immunized mice compared with Tg controls. Amyloid burden in these mice correlated inversely with plasma IgM levels. The cognitive benefit and amyloid reduction in the K6A1-30[E18E19]-vaccinated mice are likely to be related to peripheral clearance of A, because IgM does not cross the blood-brain barrier because of its large size. Our results indicate that these nontoxic A derivatives produce an attenuated antibody response, which is less likely to be associated with negative side effects while having cognitive benefits.
Key words: Mamyloid-; immunization; transgenic mice; behavior; immunoglobulin Ms; Alzheimer
Received Feb 19, 2004;
revised June 1, 2004;
accepted June 1, 2004.
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