An Attenuated Immune Response Is Sufficient to Enhance Cognition in an Alzheimer's Disease Mouse Model Immunized with Amyloid-β Derivatives

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Abstract
Immunization with amyloid-β (Aβ) 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 Aβ derivatives is much less likely to produce toxicity and have previously shown that one such derivative (K6Aβ1-30) can reduce amyloid burden in mice to a similar extent as Aβ1-42. Here, we immunized AD model mice (Tg2576) with Aβ1-30[E18E19] or with K6Aβ1-30[E18E19]. These peptides were designed to be nontoxic and to produce less T-cell response, which has been linked to toxicity. K6Aβ1-30[E18E19] induced primarily an IgM response, whereas Aβ1-30[E18E19] induced an IgG titer that was lower than previously seen with K6Aβ1-30 or Aβ1-42. However, both treated animal groups performed better than Tg controls in the radial arm maze. Amyloid burden was similar in Aβ1-30[E18E19]-vaccinated mice and their Tg controls, whereas the number of medium and small sized plaques was reduced (29-34%) in K6Aβ1-30[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 K6Aβ1-30[E18E19]-vaccinated mice are likely to be related to peripheral clearance of Aβ, because IgM does not cross the blood-brain barrier because of its large size. Our results indicate that these nontoxic Aβ derivatives produce an attenuated antibody response, which is less likely to be associated with negative side effects while having cognitive benefits.