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From The Longtine Center for Molecular Biology and Genetics,* and the W.H. Civin Laboratory for Neuropathology,** Sun Health Research Institute, Sun City, Arizona; the Department of Microbiology, Midwestern University, Glendale, Arizona; the Department of Cell Biology and Anatomy, National Cheng Kung University, Tainan, Taiwan; the Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona; the Institut de Neuropatologia,¶ Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Spain; the Department of Neurosciences,|| University of California, San Diego, La Jolla, California; and the Fundacion Instituto Leloir, Buenos Aires, Argentina
Experiments with amyloid-ß (Aß)-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 Aß-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 Aß 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 Aß deposition is still minimal. This may allow Aß mobilization under conditions in which drainage and degradation of these toxic peptides is efficient.
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