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Open Access Highly Accessed Research

Immunomodulation targeting of both Aβ and tau pathological conformers ameliorates Alzheimer’s disease pathology in TgSwDI and 3xTg mouse models

Fernando Goñi1, Krystal Herline1, Daniel Peyser1, Kinlung Wong1, Yong Ji15, Yanjie Sun1, Pankaj Mehta4 and Thomas Wisniewski1236*

Author Affiliations

1 Department of Neurology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA

2 Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA

3 Department of Psychiatry, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA

4 New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Rd., Staten Island, NY 10314, USA

5 Department of Neurology, Tianjin Huanhu Hospital, Tianjin, China

6 New York University School of Medicine, Alexandria ERSP, Rm 802, 450 East 29th Street, New York, NY 10016, USA

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Journal of Neuroinflammation 2013, 10:150  doi:10.1186/1742-2094-10-150

Published: 13 December 2013

Abstract

Background

Central to the pathogenesis of Alzheimer’s disease (AD) and many other neurodegenerative diseases is the conformational change of a normal self-protein into toxic oligomeric species and amyloid deposits. None of these disorders have an effective therapy, but immunization approaches hold great promise. We have previously shown that active immunization with a novel peptide when polymerized into a stable oligomeric conformation, pBri, induced a humoral immune response to toxic Aβ species in an AD model, APP/PS1 transgenic (Tg) mice, reducing plaque deposits. pBri is a glutaraldehyde polymerized form of the carboxyl fragment of an amyloidogenic protein, which is deposited in the brains of patients with a rare autosomal dominant disease due to a missense mutation in a stop codon, resulting in the translation of an intronic sequence, with no known sequence homology to any mammalian protein.

Methods

In the current study we tested whether pBri-peptide-based immunomodulation is effective at reducing both vascular amyloid deposits and tau-related pathology using TgSwDI mice with extensive congophilic angiopathy and 3xTg mice with tau pathology.

Results

Our results indicate that this immunomodulation approach, which produces a humoral response to proteins in a pathological conformation, is effective at reducing both Aβ and tau-related pathologies.

Conclusions

This immunomodulatory approach has the advantage of using a non-self-immunogen that is less likely to be associated with autoimmune toxicity. Furthermore we found that it is able to target all the cardinal features of AD concurrently.

Keywords:
Alzheimer’s disease; British amyloidosis; β-sheet conformation; amyloid; vaccination; transgenic mice