Abstract
Studies in transgenic mice bearing mutated human Alzheimer disease (AD) genes show that active vaccination with the amyloid beta (Abeta) protein or passive immunization with anti-Abeta antibodies has beneficial effects on the development of disease. Although a trial of Abeta vaccination in humans was halted because of autoimmune meningoencephalitis, favorable effects on Abeta deposition in the brain and on behavior were seen. Conflicting results have been observed concerning the relationship of circulating anti-Abeta antibodies and AD. Although these autoantibodies are thought to arise from exposure to Abeta, it is also possible that homologous proteins may induce antibody synthesis. We propose that the long-standing presence of anti-Abeta antibodies or antibodies to immunogens homologous to the Abeta protein may produce protective effects. The amino acid sequence of the potato virus Y (PVY) nuclear inclusion b protein is highly homologous to the immunogenic N-terminal region of Abeta. PVY infects potatoes and related crops worldwide. Here, we show through immunocytochemistry, enzyme-linked immunosorbent assay, and NMR studies that mice inoculated with PVY develop antibodies that bind to Abeta in both neuritic plaques and neurofibrillary tangles, whereas antibodies to material from uninfected potato leaf show only modest levels of background immunoreactivity. NMR data show that the anti-PVY antibody binds to Abeta within the Phe4-Ser8 and His13-Leu17 regions. Immune responses generated from dietary exposure to proteins homologous to Abeta may induce antibodies that could influence the normal physiological processing of the protein and the development or progression of AD.
Highlights
Studies in transgenic mice bearing mutated human Alzheimer disease (AD) genes show that active vaccination with the amyloid  (A) protein or passive immunization with anti-A antibodies has beneficial effects on the development of disease
The A vaccination paradigm is effective when administered either early in life, before onset of behavioral or structural evidence of the disease, or later, after disease onset [3]. Because both active vaccination with the A peptide and passive immunization with anti-A antibodies have beneficial effects [4], the potential for AD therapy is under active investigation [4]
We identified a naturally occurring protein that is highly homologous to the human A peptide and that is a nuclear inclusion b protein from a plant virus, potato virus Y (PVY) strain N (BLAST, NCBI, and National Institutes of Health), to which humans are commonly exposed
Summary
Studies in transgenic mice bearing mutated human Alzheimer disease (AD) genes show that active vaccination with the amyloid  (A) protein or passive immunization with anti-A antibodies has beneficial effects on the development of disease. In the absence of A vaccination, exposure to an immunogen that bears significant amino acid sequence homology to A could result in antibody production that has either protective or detrimental consequences (as illustrated by the studies mentioned above) To explore this hypothesis, we identified a naturally occurring protein that is highly homologous to the human A peptide and that is a nuclear inclusion b protein from a plant virus, potato virus Y (PVY) strain N (tobacco veinal necrosis) (BLAST, NCBI, and National Institutes of Health), to which humans are commonly exposed. Data are presented illustrating the biochemical nature of the binding of anti-PVY antibodies to the same region of A as is bound by therapeutic antibodies to the A protein
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