Qin Wei, Jia Jianping
Department of Neurology, Xuan Wu Hospital, Capital Medical University, Laboratory for Neurodegenerative Diseases, Ministry of Education, Beijing 100053, P.R. China.
Eur J Neurosci. 2008 May;27(9):2425-32. doi: 10.1111/j.1460-9568.2008.06207.x.
Amyloid beta (Abeta)42 plays a pivotal role in Alzheimer's disease. We previously reported a novel presenilin (PS)1 mutant (V97L) that was expressed in related patients with early onset Alzheimer's disease. We found that patients with the V97L mutation had increased levels of extracellular and intracellular Abeta42. Here we found that the increased extracellular level of Abeta42 was always accompanied by a reduction of insulin-degrading enzyme (IDE) activity on the plasma membranes. However, increase of intracellular Abeta42 was associated with decreased expression and activity of IDE in the cytosol and endoplasmic reticulum in the PS1 V97L mutant-transfected human SH-SY5Y cell line. These studies indicate that pathological levels of Abeta42 may be caused by the negative effects of PS1 (V97L) on IDE expression and activity. Our findings provide evidence for the molecular basis of familial Alzheimer's disease pathogenesis.
β淀粉样蛋白（Aβ）42在阿尔茨海默病中起关键作用。我们之前报道了一种新型早老素（PS）1突变体（V97L），它在相关早发性阿尔茨海默病患者中表达。我们发现携带V97L突变的患者细胞外和细胞内Aβ42水平升高。在此我们发现，细胞外Aβ42水平升高总是伴随着质膜上胰岛素降解酶（IDE）活性降低。然而，在转染了PS1 V97L突变体的人源SH-SY5Y细胞系中，细胞内Aβ42增加与胞质溶胶和内质网中IDE的表达及活性降低有关。这些研究表明，Aβ42的病理水平可能是由PS1（V97L）对IDE表达和活性的负面影响所致。我们的研究结果为家族性阿尔茨海默病发病机制的分子基础提供了证据。
