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(American Journal of Pathology. 2000;157:2003-2010.)
© 2000 American Society for Investigative Pathology

Regular Articles

Astroglial Expression of Human ₁-Antichymotrypsin Enhances Alzheimer-like Pathology in Amyloid Protein Precursor Transgenic Mice

Lennart Mucke^*, Gui-Qiu Yu^*, Lisa McConlogue, Edward M. Rockenstein^||, Carmela R. Abraham^§ and Eliezer Masliah^||

From the Gladstone Institute of Neurological Disease,^*
Department of Neurology,
and Neuroscience Program,
University of California San Francisco, San Francisco, California; Elan Pharmaceuticals, South San Francisco, California; the Departments of Neurosciences and Pathology,^||
University of California at San Diego, La Jolla, California; and the Departments of Biochemistry and Medicine, Boston University School of Medicine,^§
Boston, Massachusetts

Proteases and their inhibitors play key roles in physiological and pathological processes. Cerebral amyloid plaques are a pathological hallmark of Alzheimer’s disease (AD). They contain amyloid-ß (Aß) peptides in tight association with the serine protease inhibitor ₁-antichymotrypsin.^1,2 However, it is unknown whether the increased expression of ₁-antichymotrypsin found in AD brains counteracts or contributes to the disease. We used regulatory sequences of the glial fibrillary acidic protein gene³ to express human ₁-antichymotrypsin (hACT) in astrocytes of transgenic mice. These mice were crossed with transgenic mice that produce human amyloid protein precursors (hAPP) and Aß in neurons.^4,5 No amyloid plaques were found in transgenic mice expressing hACT alone, whereas hAPP transgenic mice and hAPP/hACT doubly transgenic mice developed typical AD-like amyloid plaques in the hippocampus and neocortex around 6 to 8 months of age. Co-expression of hAPP and hACT significantly increased the plaque burden at 7 to 8, 14, and 20 months. Both hAPP and hAPP/hACT mice showed significant decreases in synaptophysin-immunoreactive presynaptic terminals in the dentate gyrus, compared with nontransgenic littermates. Our results demonstrate that hACT acts as an amyloidogenic co-factor in vivo and suggest that the role of hACT in AD is pathogenic.

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