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(American Journal of Pathology. 1999;155:869-875.)
© 1999 American Society for Investigative Pathology

Regular Articles

A Role for apoE in Regulating the Levels of {alpha}-1-Antichymotrypsin in the Aging Mouse Brain and in Alzheimer's Disease

Federico Licastro*{dagger}, Iain L. Campbell{ddagger}§, Carrie Kincaid{ddagger}, Isaac Veinbergs{dagger}, Emily Van Uden{dagger}, Edward Rockenstein{dagger}, Margaret Mallory{dagger}, John R. Gilbert{ddagger} and Eliezer Masliah{dagger}

From Dipartimento di Patologia Sperimentale,*
University of Bologna, Bologna, Italy; the Departments of Neurosciences{dagger}
and Pathology,
University of California San Diego, La Jolla, California; the Department of Neuropharmacology,§
The Scripps Research Institute, La Jolla, California; and the Department of Medicine (Neurology),{ddagger}
Joseph and Katleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, North Carolina

This study was designed to explore the possible functional relationships between apolipoprotein E (apoE) and the protease inhibitor {alpha}-1-antichymotrypsin in the aging mouse brain and in Alzheimer's disease. For this purpose, levels of EB22/5 (the mouse homologue to human {alpha}-1-antichymotrypsin) mRNA expression was studied in apoE-deficient mice. These mice showed an age-dependent increase of EB22/5 mRNA expression in the brain. Furthermore, overexpression of allele 3 of human APOE gene in transgenic mice (in an apoE-deficient background) resulted in normalization of levels of EB22/5 mRNA expression compatible with levels found in control mice. In contrast, overexpression of human APOE4 allele or down-regulation of the apoE receptor low density lipoprotein receptor-related protein by deletion of the receptor-associated protein was associated with elevated levels of EB22/5 similar to apoE-deficient mice. Consistent with the findings in murine models, human {alpha}-1-antichymotrypsin protein was increased in brain homogenates from patients with Alzheimer's disease, and levels of this serpin were the highest in patients with the APOE4 allele. In summary, the present study showed evidence supporting a role for apoE in regulating {alpha}-1-antichymotrypsin expression. This is relevant to Alzheimer's disease because these two molecules appear to be closely associated with the pathogenesis of this disorder.






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Copyright © 1999 by the American Society for Investigative Pathology.