Lechner Theresa, Adlassnig Christine, Humpel Christian, Kaufmann Walter A, Maier Hans, Reinstadler-Kramer Karin, Hinterhölzl Josef, Mahata Sushil K, Jellinger Kurt A, Marksteiner Josef
Department of Psychiatry, Anichstrasse 35, Innsbruck A-6020, Austria.
Exp Gerontol. 2004 Jan;39(1):101-13. doi: 10.1016/j.exger.2003.09.018.
Synaptic disturbances may play a key role in the pathophysiology of Alzheimer's disease. To characterize differential synaptic alterations in the brains of Alzheimer patients, chromogranin A, chromogranin B and secretoneurin were applied as soluble constituents for large dense core vesicles, synaptophysin as a vesicle membrane marker and calbindin as a cytosolic protein. In controls, chromogranin B and secretogranin are largely co-contained in interneurons, whereas chromogranin A is mostly found in pyramidal neurons. In Alzheimer's disease, about 30% of beta-amyloid plaques co-labelled with chromogranin A, 20% with secretoneurin and 15% with chromogranin B. Less than 5% of beta-amyloid plaques contained synaptophysin or calbindin, respectively. Semiquantitative immunohistochemistry revealed a significant loss for chromogranin B- and secretoneurin-like immunoreactivity in the dorsolateral, the entorhinal, and orbitofrontal cortex. Chromogranin A displayed more complex changes. It was the only chromogranin peptide to be expressed in glial fibrillary acidic protein containing cells. About 40% of chromogranin A immunopositive plaques and extracellular deposits were surrounded and pervaded by activated microglia. The present study demonstrates a loss of presynaptic proteins involved in distinct steps of exocytosis. An imbalanced availability of chromogranins may be responsible for impaired neurotransmission and a reduced functioning of dense core vesicles. Chromogranin A is likely to be a mediator between neuronal, glial and inflammatory mechanisms found in Alzheimer disease.
突触紊乱可能在阿尔茨海默病的病理生理学中起关键作用。为了表征阿尔茨海默病患者大脑中不同的突触改变，将嗜铬粒蛋白A、嗜铬粒蛋白B和分泌粒蛋白作为大致密核心囊泡的可溶性成分，将突触素作为囊泡膜标记物，将钙结合蛋白作为胞质蛋白。在对照组中，嗜铬粒蛋白B和分泌粒蛋白主要共同存在于中间神经元中，而嗜铬粒蛋白A大多存在于锥体细胞中。在阿尔茨海默病中，约30%的β-淀粉样斑块与嗜铬粒蛋白A共同标记，20%与分泌粒蛋白共同标记，15%与嗜铬粒蛋白B共同标记。分别少于5%的β-淀粉样斑块含有突触素或钙结合蛋白。半定量免疫组织化学显示，在背外侧、内嗅和眶额皮质中，嗜铬粒蛋白B和分泌粒蛋白样免疫反应性显著丧失。嗜铬粒蛋白A表现出更复杂的变化。它是唯一在含有胶质纤维酸性蛋白的细胞中表达的嗜铬粒蛋白肽。约40%的嗜铬粒蛋白A免疫阳性斑块和细胞外沉积物被活化的小胶质细胞包围并弥漫。本研究表明参与胞吐不同步骤的突触前蛋白丧失。嗜铬粒蛋白可用性的失衡可能导致神经传递受损和致密核心囊泡功能降低。嗜铬粒蛋白A可能是阿尔茨海默病中发现的神经元、胶质和炎症机制之间的介质。
