Nistor M, Don M, Parekh M, Sarsoza F, Goodus M, Lopez G E, Kawas C, Leverenz J, Doran E, Lott I T, Hill M, Head E
Institute for Brain Aging & Dementia, CA, United States.
Neurobiol Aging. 2007 Oct;28(10):1493-506. doi: 10.1016/j.neurobiolaging.2006.06.023. Epub 2006 Aug 9.
Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months-69 years) and in 26 controls (5 months-100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alpha-secretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Abeta) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Abeta degradation and clearance.
患有唐氏综合征（DS）的老年人在40岁时会出现阿尔茨海默病（AD）神经病理学特征。本研究的目的是测量36名DS患者（年龄在5个月至69岁之间）和26名对照者（年龄在5个月至100岁之间）中与年龄相关的APP加工变化。在DS患者中，α-分泌酶活性随年龄显著降低，尤其是在40岁以上的患者中，而在对照者中则保持稳定。反映α-分泌酶加工的APP C末端片段（CTF-α）水平在两组中均随年龄下降。在两组中，β-分泌酶活性均随年龄显著增加。在对照者中，CTF-β水平随年龄保持恒定，提示周转/清除机制的代偿性增加。在DS患者中，年轻个体的CTF-β水平最低，这可能反映了β-淀粉样蛋白（Aβ）向可溶性池的快速转化或有效的CTF-β清除机制。如果将针对分泌酶活性的治疗与增强Aβ降解和清除的方法相结合，那么在一般人群中用于延缓或预防AD的治疗方法可能对患有DS的成年人更有效。
