Amyloid-β peptide remnants in AN-1792-immunized Alzheimer's disease patients: A biochemical analysis

R. Lyle Patton, Walter M. Kalback, Chera L. Esh, Tyler A. Kokjohn, Gregory D. Van Vickle, Dean C. Luehrs, Yu Min Kuo, John Lopez, Daniel Brune, Isidro Ferrer, Eliezer Masliah, Amanda J. Newel, Thomas G. Beach, Eduardo M. Castaño, Alex E. Roher

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160 Citations (Scopus)

Abstract

Experiments with amyloid-β (Aβ)-42-immunized transgenic mouse models of Alzheimer's disease have revealed amyloid plaque disruption and apparent cognitive function recovery. Neuropathological examination of patients vaccinated against purified Aβ-42 (AN-1792) has demonstrated that senile plaque disruption occurred in immunized humans as well. Here, we examined tissue histology and quantified and biochemically characterized the remnant amyloid peptides in the gray and white matter and leptomeningeal/cortical vessels of two AN-1792-vaccinated patients, one of whom developed meningoencephalitis. Compact core and diffuse amyloid deposits in both vaccinated individuals were focally absent in some regions. Although parenchymal amyloid was focally disaggregated, vascular deposits were relatively preserved or even increased. Immunoassay revealed that total soluble amyloid levels were sharply elevated in vaccinated patient gray and white matter compared with Alzheimer's disease cases. Our experiments suggest that although immunization disrupted amyloid deposits, vascular capture prevented large-scale egress of Aβ peptides. Trapped, solubilized amyloid peptides may ultimately have cascading toxic effects on cerebrovascular, gray and white matter tissues. Anti-amyloid immunization may be most effective not as therapeutic or mitigating measures but as a prophylactic measure when Aβ deposition is still minimal. This may allow Aβ mobilization under conditions in which drainage and degradation of these toxic peptides is efficient.

Original languageEnglish
Pages (from-to)1048-1063
Number of pages16
JournalAmerican Journal of Pathology
Volume169
Issue number3
DOIs
Publication statusPublished - 2006 Sep

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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    Patton, R. L., Kalback, W. M., Esh, C. L., Kokjohn, T. A., Van Vickle, G. D., Luehrs, D. C., Kuo, Y. M., Lopez, J., Brune, D., Ferrer, I., Masliah, E., Newel, A. J., Beach, T. G., Castaño, E. M., & Roher, A. E. (2006). Amyloid-β peptide remnants in AN-1792-immunized Alzheimer's disease patients: A biochemical analysis. American Journal of Pathology, 169(3), 1048-1063. https://doi.org/10.2353/ajpath.2006.060269