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

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.

• Authors: Fernando Goñi, Krystal Herline, Daniel Peyser, Kinlung Wong, Yong Ji, Yanjie Sun, Pankaj Mehta, Thomas Wisniewski
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 10 Pg. 150 (Dec 13 2013) ISSN: 1742-2094 [Electronic] England
• PMID: 24330773 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Amyloidogenic Proteins
• tau Proteins

Topics

• Alzheimer Disease (immunology, pathology)
• Amyloid beta-Peptides (immunology)
• Amyloidogenic Proteins (chemistry, immunology)
• Animals
• Blotting, Western
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Humans
• Immunization
• Luminescent Measurements
• Mice
• Mice, Transgenic
• Molecular Mimicry
• Protein Structure, Secondary
• tau Proteins (immunology)