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The Journal of Neuroscience, March 1, 2001, 21(5):1444-1451

-1-Antichymotrypsin Promotes -Sheet Amyloid Plaque Deposition in a Transgenic Mouse Model of Alzheimer's Disease

Lars N. G. Nilsson^{1, 2, 3}, Kelly R. Bales⁵, Giovanni DiCarlo⁴, Marcia N. Gordon⁴, Dave Morgan⁴, Steven M. Paul⁵, and Huntington Potter^{1, 2, 3}

¹ Suncoast Gerontology Center, ² Department of Biochemistry and Molecular Biology, ³ Moffitt Cancer Center, and ⁴ Department of Pharmacology, College of Medicine, University of South Florida, Tampa, Florida 33612, and ⁵ Neuroscience Discovery Research, Lilly Research Laboratories, Indianapolis, Indiana 46285

₁-Antichymotrypsin (ACT), an acute-phase inflammatory protein, is an integral component of the amyloid deposits in Alzheimer's disease (AD) and has been shown to catalyze amyloid -peptide polymerization in vitro. We have investigated the impact of ACT on amyloid deposition in vivo by generating transgenic GFAP-ACT-expressing mice and crossing them with the PDGF-hAPP/V717F mice, which deposit amyloid in an age-dependent manner. The number of amyloid deposits measured by Congo Red birefringence was increased in the double ACT/amyloid precursor protein (APP) transgenic mice compared with transgenic mice that only expressed APP, particularly in the hippocampus where ACT expression was highest, and the increase was preceded by elevated total amyloid -peptide levels at an early age. Our data demonstrate that ACT promotes amyloid deposition and provide a specific mechanism by which inflammation and the subsequent upregulation of astrocytic ACT expression in AD brain contributes to AD pathogenesis.

Key words: 1-antichymotrypsin; Alzheimer's disease; amyloid deposition; inflammation; transgenic mice; amyloid -peptide; Congo Red

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2151444-08$05.00/0

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