Astroglial expression of human alpha(1)-antichymotrypsin enhances Alzheimer-like pathology in amyloid protein precursor transgenic mice

Proteases and their inhibitors play key roles in physiological and patholog ical processes. Cerebral amyloid plaques are a pathological hallmark of Alz heimer's disease (AD). They contain amyloid-beta (A beta) peptides in tight association with the serine protease inhibitor alpha (1)-antichymotrypsin. (1,2) However, it is unknown whether the increased expression of alpha (1)- antichymotrypsin found in AD brains counteracts or contributes to the disea se. We used regulatory sequences of the glial fibrillary acidic protein gen e(3) to express human alpha (1)-antichymotrypsin (hACT) in astrocytes of tr ansgenic mice. These mice were crossed with transgenic mice that produce hu man amyloid protein precursors (hAPP) and A beta in neurons.(4,5) No amyloi d 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 si gnificant decreases in synaptophysin-immunoreactive presynaptic terminals i n the dentate gyrus, compared with nontransgenic littermates. Our results d emonstrate that hACT acts as an amyloidogenic co-factor in vivo and suggest that the role of hACT in AD is pathogenic.