Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P
Elan Pharmaceuticals, South San Francisco, California 94080, USA.
Nature. 1999 Jul 8;400(6740):173-7. doi: 10.1038/22124.
Amyloid-beta peptide (Abeta) seems to have a central role in the neuropathology of Alzheimer's disease (AD). Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes. Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (Abeta42), which is the predominant form found in the amyloid plaques of Alzheimer's disease. The PDAPP transgenic mouse, which overexpresses mutant human APP (in which the amino acid at position 717 is phenylalanine instead of the normal valine), progressively develops many of the neuropathological hallmarks of Alzheimer's disease in an age- and brain-region-dependent manner. In the present study, transgenic animals were immunized with Abeta42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-beta deposition and several of the subsequent neuropathological changes were well established. We report that immunization of the young animals essentially prevented the development of beta-amyloid-plaque formation, neuritic dystrophy and astrogliosis. Treatment of the older animals also markedly reduced the extent and progression of these AD-like neuropathologies. Our results raise the possibility that immunization with amyloid-beta may be effective in preventing and treating Alzheimer's disease.
β-淀粉样肽（Aβ）似乎在阿尔茨海默病（AD）的神经病理学中起核心作用。该疾病的家族形式与淀粉样前体蛋白（APP）和早老素基因的突变有关。这些基因中与疾病相关的突变导致42个氨基酸形式的肽（Aβ42）产生增加，而Aβ42是在阿尔茨海默病淀粉样斑块中发现的主要形式。PDAPP转基因小鼠过度表达突变型人类APP（其中第717位氨基酸是苯丙氨酸而非正常的缬氨酸），会以年龄和脑区依赖的方式逐渐出现许多阿尔茨海默病的神经病理学特征。在本研究中，对转基因动物用Aβ42进行免疫，要么在AD型神经病理学症状出现之前（6周龄时），要么在年龄较大时（11个月），此时β-淀粉样蛋白沉积和一些随后的神经病理学变化已经很明显。我们报告称，对幼年动物进行免疫基本上可预防β-淀粉样斑块形成、神经纤维营养不良和星形胶质细胞增生的发展。对老年动物进行治疗也显著降低了这些类AD神经病理学症状的程度和进展。我们的结果提出了用β-淀粉样蛋白进行免疫可能有效预防和治疗阿尔茨海默病的可能性。
