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 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 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 disease. We used regulatory sequences of the glial fibrillary acidic protein gene(3) to express human alpha(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.
Mucke
L
L
Gladstone Institute of Neurological Disease, Department of Neurology, and Neuroscience Program, University of California San Francisco, San Francisco, California, USA. Lmucke@gladstone.ucsf.edu
Yu
G Q
GQ
McConlogue
L
L
Rockenstein
E M
EM
Abraham
C R
CR
Masliah
E
E
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic / Q000235:genetics; D058225:Plaque, Amyloid / Q000473:pathology; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects; D019076:Transgenes / Q000235:genetics; D000514:alpha 1-Antichymotrypsin / Q000235:genetics / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015842:Serine Proteinase Inhibitors; D000514:alpha 1-Antichymotrypsin