Immunization with amyloid-β attenuates Alzheimer disease-like pathology in the PDAPP mouse
Immunization with amyloid-β attenuates Alzheimer disease-like pathology in the PDAPP mouse
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DOI：
10.1038/22124
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发表时间：
1999-07-08
期刊：
影响因子：
64.8
通讯作者：
Seubert, P
中科院分区：
文献类型：
--
作者：
Schenk, D;Barbour, R;Seubert, P
淀粉样β蛋白(Aβ)似乎在阿尔茨海默病(AD)的神经病理中起核心作用(1)。这种疾病的家族性形式与淀粉样前体蛋白(APP)和早老素基因(2，3)的突变有关。这些基因与疾病相关的突变导致42氨基酸形式的多肽(Aβ(42))(4-8)的产生增加，这是在阿尔茨海默病(9，10)的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的人类APP(其中717位的氨基酸是苯丙氨酸而不是正常的缬氨酸)，以年龄和大脑区域依赖的方式逐渐发展为阿尔茨海默病的许多神经病理特征(11，12)。在目前的研究中，转基因动物被免疫Aβ(42)，要么是在AD类型的神经病变开始之前(6周大)，要么是在较大的年龄(11个月大)，那时淀粉样β蛋白沉积和几个随后的神经病理变化被很好地确立。我们报告说，幼年动物的免疫从根本上防止了β-淀粉样斑块形成、神经炎性营养不良和星形胶质细胞增生症的发展。对老年动物的治疗也显著减少了这些AD样神经病变的程度和进展。我们的结果增加了用淀粉样β蛋白免疫可能在预防和治疗阿尔茨海默病方面有效的可能性。
Amyloid-beta peptide (A beta) seems to have a central role in the neuropathology of Alzheimer's disease (AD)(1). Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes(2,3). Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (A beta(42))(4-8), which is the predominant form found in the amyloid plaques of Alzheimer's disease(9,10). 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(11,12). In the present study, transgenic animals were immunized with A beta(42), 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.