The pathological process underlying Alzheimer's disease in individuals under thirty
The pathological process underlying Alzheimer's disease in individuals under thirty
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DOI：
10.1007/s00401-010-0789-4
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发表时间：
2011-02-01
影响因子：
12.7
通讯作者：
Del Tredici, Kelly
中科院分区：
文献类型：
--
作者：
Braak, Heiko;Del Tredici, Kelly
使用抗体（AT8、4G8）和银染法对42名年龄在4岁至29岁之间的个体的大脑进行检查，以确定是否存在与阿尔茨海默病相关的神经元内和细胞外蛋白质聚集体。42例中有38例（38/42）在神经细胞或其细胞突起的部分显示出异常磷酸化的tau蛋白（前缠结物质），41/42的个体未显示细胞外β -淀粉样蛋白沉积或神经炎性斑块——只有一名唐氏综合征患者例外。在42例中有16例在内嗅皮质区发现异常tau蛋白，在42例中有3例该部位对孤立的神经原纤维缠结（NFT阶段I）呈加利亚斯阳性。在26例内嗅皮质区未发现异常tau蛋白的病例中，4例在皮质下部位未显示前缠结物质。然而，这26例中的其余22例，其皮质下病变局限于非丘脑核，这些核向大脑皮质有弥散性投射，而且值得注意的是，在22例中有19例前缠结物质局限于去甲肾上腺素能蓝斑/蓝斑下复合体。假设前缠结改变不是暂时的且不会消退，这些发现可能表明导致神经原纤维缠结形成的阿尔茨海默病相关病理过程并非始于大脑皮质，而是始于特定的皮质下核，并且可能开始得相当早，即在青春期之前或成年早期。
Brains of 42 individuals between the ages of 4 and 29 were examined with antibodies (AT8, 4G8) and silver stains for the presence of intraneuronal and extracellular protein aggregates associated with Alzheimer's disease. Thirty-eight of 42 (38/42) cases displayed abnormally phosphorylated tau protein (pretangle material) in nerve cells or in portions of their cellular processes, and 41/42 individuals showed no extracellular amyloid-beta protein deposition or neuritic plaques-an individual with Down syndrome was the only exception. In 16/42 cases abnormal tau was found in the transentorhinal region, and in 3/42 cases this site was Gallyas-positive for isolated NFTs (NFT stage I). Of 26 cases that lacked abnormal tau in the transentorhinal region, 4 did not show pretangle material at subcortical sites. The remaining 22 of these same 26 cases, however, had subcortical lesions confined to non-thalamic nuclei with diffuse projections to the cerebral cortex, and, remarkably, in 19/22 individuals the pretangle material was confined to the noradrenergic coeruleus/subcoeruleus complex. Assuming the pretangle alterations are not transient and do not regress, these findings may indicate that the Alzheimer's disease-related pathological process leading to neurofibrillary tangle formation does not begin in the cerebral cortex but, rather, in select subcortical nuclei, and it may start quite early, i.e., before puberty or in early young adulthood.