Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes
Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes
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DOI：
10.1038/nm0198-097
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发表时间：
1998-01-01
期刊：
影响因子：
82.9
通讯作者：
Duff, K
中科院分区：
文献类型：
--
作者：
Holcomb, L;Gordon, MN;Duff, K
阿尔茨海默病(AD)的遗传原因包括淀粉样前体蛋白(APP)、早老素1(PS1)和早老素2(PS2)基因的突变(1)。突变的APP(K670N，M671L)转基因系Tg2576在幼年时显示出显著的淀粉样β蛋白(Aβ)水平升高，并在9-12个月时在大脑皮层和海马区形成细胞外AD-Aβ沉积(2)。突变的PS1转基因小鼠没有表现出异常的病理，但确实表现出高度淀粉样变性42或43氨基酸的Aβ42(43)水平的微妙升高(参考文献。3)。在这里，我们证明了Tg2576与突变的PS1(M146L)转基因系杂交的双转基因后代在大脑皮层和海马区形成了大量的纤维Aβ沉积，远远早于其单一转基因Tg2576的后代。在显性Aβ沉积之前的一段时间里，双转基因小鼠大脑中的Aβ42(43)选择性增加了41%。因此，当PS1突变导致Aβ42(43)适度增加时，当PS1突变被引入Tg2576来源的小鼠中时，AD样病理的发展显著增强。值得注意的是，在Aβ沉积明显之前，双转基因和单转基因小鼠在“Y”迷宫中的自发交替能力都有所降低。这表明这些小鼠的行为表型的某些方面可能与斑块形成之前的事件有关。
Genetic causes of Alzheimer's disease (AD) include mutations in the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes(1). The mutant APP(K670N,M671L) transgenic line, Tg2576, shows markedly elevated amyloid beta-protein (A beta) levels at an early age and, by 9-12 months, develops extracellular AD-type A beta deposits in the cortex and hippocampus(2). Mutant PS1 transgenic mice do not show abnormal pathology, but do display subtly elevated levels of the highly amyloidogenic 42- or 43-amino acid peptide A beta 42(43) (ref. 3). Here we demonstrate that the doubly transgenic progeny from a cross between line Tg2576 and a mutant PS1(M146L) transgenic line develop large numbers of fibrillar A beta deposits in cerebral cortex and hippocampus far earlier than their singly transgenic Tg2576 littermates. In the period preceding overt A beta deposition, the doubly transgenic mice show a selective 41% increase in A beta 42(43) in their brains. Thus, the development of AD-like pathology is substantially enhanced when a PS1 mutation, which causes a modest increase in A beta 42(43), is introduced into Tg2576-derived mice. Remarkably, both doubly and singly transgenic mice showed reduced spontaneous alternation performance in a "Y" maze before substantial A beta deposition was apparent. This suggests that some aspects of the behavioral phenotype in these mice may be related to an event that precedes plaque formation.