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Vaccination of Alzheimer's model mice with Aβ derivative in alum adjuvant reduces Aβ burden without microhemorrhages

Authors

  • Ayodeji A. Asuni,

    1. Department of Psychiatry, New York University School of Medicine, Millhauser Laboratories, 560 First Avenue, New York, NY 10016, USA
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  • Allal Boutajangout,

    1. Department of Psychiatry, New York University School of Medicine, Millhauser Laboratories, 560 First Avenue, New York, NY 10016, USA
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  • Henrieta Scholtzova,

    1. Pathology, New York University School of Medicine, 560 First Avenue, New York, NY 10016, USA
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  • Elin Knudsen,

    1. Department of Psychiatry, New York University School of Medicine, Millhauser Laboratories, 560 First Avenue, New York, NY 10016, USA
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  • Yong Sheng Li,

    1. Pathology, New York University School of Medicine, 560 First Avenue, New York, NY 10016, USA
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  • David Quartermain,

    1. Pathology, New York University School of Medicine, 560 First Avenue, New York, NY 10016, USA
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  • Blas Frangione,

    1. Department of Psychiatry, New York University School of Medicine, Millhauser Laboratories, 560 First Avenue, New York, NY 10016, USA
    2. Neurology, New York University School of Medicine, Millhauser Laboratories, 560 First Avenue, New York, NY 10016, USA
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  • Thomas Wisniewski,

    1. Department of Psychiatry, New York University School of Medicine, Millhauser Laboratories, 560 First Avenue, New York, NY 10016, USA
    2. Pathology, New York University School of Medicine, 560 First Avenue, New York, NY 10016, USA
    3. Neurology, New York University School of Medicine, Millhauser Laboratories, 560 First Avenue, New York, NY 10016, USA
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  • Einar M. Sigurdsson

    1. Department of Psychiatry, New York University School of Medicine, Millhauser Laboratories, 560 First Avenue, New York, NY 10016, USA
    2. Neurology, New York University School of Medicine, Millhauser Laboratories, 560 First Avenue, New York, NY 10016, USA
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Dr Einar M. Sigurdsson, 1Department of Psychiatry, or Thomas Wisniewski, 3Department of Neurology, as above.
Email: einar.sigurdsson@med.nyu.edu
or thomas.wisniewski@med.nyu.edu

Abstract

Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. The meningoencephalitis observed in the first AD vaccination trial was likely related to excessive cell-mediated immunity caused by the immunogen, amyloid-β (Aβ) 1–42, and the adjuvant, QS−21. To avoid this toxicity, we have been using Aβ derivatives in alum adjuvant that promotes humoral immunity. Other potential side effects of immunotherapy are increased vascular amyloid and associated microhemorrhages that may be related to rapid clearance of parenchymal amyloid. Here, we determined if our immunization strategy was associated with this form of toxicity, and if the therapeutic effect was age-dependent. Tg2576 mice and wild-type littermates were immunized from 11 or 19 months and their behaviour evaluated prior to killing at 24 months. Subsequently, plaque- and vascular-Aβ burden, Aβ levels and associated pathology was assessed. The therapy started at the cusp of amyloidosis reduced cortical Aβ deposit burden by 31% and Aβ levels by 30–37%, which was associated with cognitive improvements. In contrast, treatment from 19 months, when pathology is well established, was not immunogenic and therefore did not reduce Aβ burden or improve cognition. Significantly, the immunotherapy in the 11–24 months treatment group, that reduced Aβ burden, did not increase cerebral bleeding or vascular Aβ deposits in contrast to several Aβ antibody studies. These findings indicate that our approach age-dependently improves cognition and reduces Aβ burden when used with an adjuvant suitable for humans, without increasing vascular Aβ deposits or microhemorrhages.

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