A role for apoE in regulating the levels of alpha-1-antichymotrypsin in the aging mouse brain and in Alzheimer's disease

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