Hyman B T, Tanzi R E, Marzloff K, Barbour R, Schenk D
Neurology Service, Massachusetts General Hospital, Harvard Medical School, Boston 02114.
J Neuropathol Exp Neurol. 1992 Jan;51(1):76-83. doi: 10.1097/00005072-199201000-00009.
The amyloid beta protein (beta/A4) that is deposited in senile plaques and in cerebral vessels in Alzheimer's disease (AD) is derived from a larger membrane-associated glycoprotein, the amyloid beta protein precursor (APP). The gene encoding APP produces at least four major transcripts. Three of the four transcripts contain an alternatively-spliced exon encoding a Kunitz protease inhibitor domain (KPI). We now report the results of a series of experiments using novel immunohistochemical reagents to anatomically localize beta/A4, APP, and KPI-containing forms of APP (APP-KPI) in the hippocampal formation and temporal neocortex. A new monoclonal antibody against beta/A4 recognized senile plaques and vascular amyloid, but no cellular elements. Anti-APP and anti-KPI monoclonal antibodies stained neurons, including proximal axons and dendrites. The neuritic component of some plaques in patients with AD and in elderly control individuals were also immunoreactive for both APP and APP-KPI. Quantitative assessment of senile plaques in temporal neocortex showed that, on average, about one-third of beta/A4 immunoreactive plaques stained with either anti-APP or anti-KPI. Amyloid beta protein precursor and APP-KPI immunoreactivity were also found in the white and grey matter vessels of both AD patients and control individuals. These results suggest that KPI-containing forms of APP are present in dystrophic neurites of senile plaques, and normally in neurons, neuronal processes, and in the vascular compartment in the brain. Thus, APP-KPI is in a position to be intimately associated with beta/A4 deposition in the neuropil, in plaques and in amyloid angiopathy.
沉积于阿尔茨海默病（AD）患者老年斑和脑血管中的β淀粉样蛋白（β/A4）源自一种更大的膜相关糖蛋白——淀粉样β蛋白前体（APP）。编码APP的基因至少产生四种主要转录本。这四种转录本中的三种含有一个选择性剪接的外显子，该外显子编码一个库尼茨蛋白酶抑制剂结构域（KPI）。我们现在报告一系列实验的结果，这些实验使用新型免疫组织化学试剂在海马结构和颞叶新皮质中对β/A4、APP以及含KPI的APP形式（APP-KPI）进行解剖定位。一种针对β/A4的新单克隆抗体识别老年斑和血管淀粉样蛋白，但不识别细胞成分。抗APP和抗KPI单克隆抗体对神经元进行染色，包括近端轴突和树突。AD患者和老年对照个体中一些斑块的神经炎性成分对APP和APP-KPI也具有免疫反应性。对颞叶新皮质中老年斑的定量评估表明，平均而言，约三分之一的β/A4免疫反应性斑块用抗APP或抗KPI染色。在AD患者和对照个体的白质和灰质血管中也发现了淀粉样β蛋白前体和APP-KPI免疫反应性。这些结果表明，含KPI的APP形式存在于老年斑的营养不良性神经突中，正常情况下存在于神经元、神经突起以及脑内的血管区室中。因此，APP-KPI可能与神经毡、斑块和淀粉样血管病中的β/A4沉积密切相关。
