Mucke L, Yu G Q, McConlogue L, Rockenstein E M, Abraham C R, Masliah E
Gladstone Institute of Neurological Disease, Department of Neurology, and Neuroscience Program, University of California San Francisco, San Francisco, California, USA.
Am J Pathol. 2000 Dec;157(6):2003-10. doi: 10.1016/s0002-9440(10)64839-0.
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.
蛋白酶及其抑制剂在生理和病理过程中发挥着关键作用。脑淀粉样斑块是阿尔茨海默病（AD）的病理标志。它们含有与丝氨酸蛋白酶抑制剂α1 - 抗糜蛋白酶紧密结合的淀粉样β（Aβ）肽。（1,2）然而，在AD大脑中发现的α1 - 抗糜蛋白酶表达增加是抵消还是促进了该疾病尚不清楚。我们利用胶质纤维酸性蛋白基因的调控序列（3）在转基因小鼠的星形胶质细胞中表达人α1 - 抗糜蛋白酶（hACT）。这些小鼠与在神经元中产生人淀粉样蛋白前体（hAPP）和Aβ的转基因小鼠杂交。（4,5）单独表达hACT的转基因小鼠未发现淀粉样斑块，而hAPP转基因小鼠和hAPP/hACT双转基因小鼠在6至8个月大时在海马体和新皮质中出现了典型的AD样淀粉样斑块。hAPP和hACT的共表达在7至8个月、14个月和20个月时显著增加了斑块负担。与非转基因同窝小鼠相比，hAPP和hAPP/hACT小鼠在齿状回中突触素免疫反应性突触前终末均显著减少。我们的结果表明，hACT在体内作为淀粉样蛋白生成的辅助因子，提示hACT在AD中的作用是致病的。
