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Novel Aβ peptide immunogens modulate plaque pathology and inflammation in a murine model of Alzheimer's disease

Authors
  • Zhou, Jun1
  • Fonseca, Maria I1
  • Kayed, Rakez1
  • Hernandez, Irma1
  • Webster, Scott D2
  • Yazan, Ozkan1
  • Cribbs, David H3, 4
  • Glabe, Charles G1, 4
  • Tenner, Andrea J1, 4, 5
  • 1 University of California, Department of Molecular Biology and Biochemistry, Irvine, CA, 92697, USA , Irvine
  • 2 Clarient, Inc., San Juan Capistrano, CA, 92675, USA , San Juan Capistrano
  • 3 University of California, Irvine, College of Medicine, Department of Neurology, Irvine, CA, 92697, USA , Irvine
  • 4 University of California, Institute for Brain Aging and Dementia, Irvine, CA, 92697, USA , Irvine
  • 5 University of California, Center for Immunology, Irvine, CA, 92697, USA , Irvine
Type
Published Article
Journal
Journal of Neuroinflammation
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Dec 07, 2005
Volume
2
Issue
1
Identifiers
DOI: 10.1186/1742-2094-2-28
Source
Springer Nature
Keywords
License
Yellow

Abstract

BackgroundAlzheimer's disease, a common dementia of the elder, is characterized by accumulation of protein amyloid deposits in the brain. Immunization to prevent this accumulation has been proposed as a therapeutic possibility, although adverse inflammatory reactions in human trials indicate the need for novel vaccination strategies.MethodHere vaccination with novel amyloid peptide immunogens was assessed in a transgenic mouse model displaying age-related accumulation of fibrillar plaques.ResultsImmunization with any conformation of the amyloid peptide initiated at 12 months of age (at which time fibrillar amyloid has just begun to accumulate) showed significant decrease in total and fibrillar amyloid deposits and in glial reactivity relative to control transgenic animals. In contrast, there was no significant decrease in amyloid deposition or glial activation in mice in which vaccination was initiated at 16 months of age, despite the presence of similar levels anti-Aβ antibodies in young and old animals vaccinated with a given immunogen. Interestingly, immunization with an oligomeric conformation of Aβ was equally as effective as other amyloid peptides at reducing plaque accumulation. However, the antibodies generated by immunization with the oligomeric conformation of Aβ have more limited epitope reactivity than those generated by fAβ, and the microglial response was significantly less robust.ConclusionThese results suggest that a more specific immunogen such as oligomeric Aβ can be designed that achieves the goal of depleting amyloid while reducing potential detrimental inflammatory reactions. In addition, the data show that active immunization of older Tg2576 mice with any amyloid conformation is not as efficient at reducing amyloid accumulation and related pathology as immunization of younger mice, and that serum anti-amyloid antibody levels are not quantitatively related to reduced amyloid-associated pathology.

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