Lee M K, Slunt H H, Martin L J, Thinakaran G, Kim G, Gandy S E, Seeger M, Koo E, Price D L, Sisodia S S
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Neurosci. 1996 Dec 1;16(23):7513-25. doi: 10.1523/JNEUROSCI.16-23-07513.1996.
Mutations in genes encoding related proteins, termed presenilin 1 (PS1) and presenilin 2 (PS2), are linked to the majority of cases with early-onset familial Alzheimer's disease (FAD). To clarify potential function(s) of presenilins and relationships of presenilin expression to pathogenesis of AD, we examined the expression of PS1 and PS2 mRNA and PS1 protein in human and mouse. Semi-quantitative PCR of reverse-transcribed RNA (RT-PCR) analysis revealed that PS1 and PS2 mRNA are expressed ubiquitously and at comparable levels in most human and mouse tissues, including adult brain. However, PS1 mRNA is expressed at significantly higher levels in developing brain. In situ hybridization studies of mouse embryos revealed widespread expression of PS1 mRNA with a neural expression pattern that, in part, overlaps that reported for mRNA encoding specific Notch homologs. In situ hybridization analysis in adult mouse brain revealed that PS1 and PS2 mRNAs are enriched in neurons of the hippocampal formation and entorhinal cortex. Although PS1 and PS2 mRNA are expressed most prominently in neurons, lower but significant levels of PS1 and PS2 transcripts are also detected in white matter glial cells. Moreover, cultured neurons and astrocytes express PS1 and PS2 mRNAs. Using PS1-specific antibodies in immunoblot analysis, we demonstrate that PS1 accumulates as approximately 28 kDa N-terminal and approximately 18 kDa C-terminal fragments in brain. Immunocytochemical studies of mouse brain reveal that PS1 protein accumulates in a variety of neuronal populations with enrichment in somatodendritic and neuropil compartments.
编码相关蛋白的基因发生突变，这些蛋白被称为早老素1（PS1）和早老素2（PS2），与大多数早发性家族性阿尔茨海默病（FAD）病例相关。为了阐明早老素的潜在功能以及早老素表达与阿尔茨海默病发病机制的关系，我们检测了人和小鼠中PS1和PS2 mRNA以及PS1蛋白的表达。逆转录RNA（RT-PCR）分析的半定量PCR结果显示，PS1和PS2 mRNA在包括成人大脑在内的大多数人和小鼠组织中普遍表达且水平相当。然而，PS1 mRNA在发育中的大脑中表达水平显著更高。对小鼠胚胎的原位杂交研究显示PS1 mRNA广泛表达，其神经表达模式部分与报道的编码特定Notch同源物的mRNA的表达模式重叠。对成年小鼠大脑的原位杂交分析显示，PS1和PS2 mRNA在海马结构和内嗅皮质的神经元中富集。虽然PS1和PS2 mRNA在神经元中表达最为显著，但在白质胶质细胞中也检测到较低但显著水平的PS1和PS2转录本。此外，培养的神经元和星形胶质细胞表达PS1和PS2 mRNA。在免疫印迹分析中使用PS1特异性抗体，我们证明PS1在大脑中以约28 kDa的N端片段和约18 kDa的C端片段形式积累。对小鼠大脑的免疫细胞化学研究显示，PS1蛋白在多种神经元群体中积累，在胞体树突和神经毡区室中富集。
