Matsui Toshifumi, Ingelsson Martin, Fukumoto Hiroaki, Ramasamy Karunya, Kowa Hisatomo, Frosch Matthew P, Irizarry Michael C, Hyman Bradley T
Alzheimer Disease Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Brain Res. 2007 Aug 3;1161:116-23. doi: 10.1016/j.brainres.2007.05.050. Epub 2007 Jun 5.
In both trisomy 21 and rare cases of triplication of amyloid precursor protein (APP) Alzheimer's disease (AD) pathological changes are believed to be secondary to increased expression of APP. We hypothesized that sporadic AD may also be associated with changes in transcription of APP or its metabolic partners. To address this issue, temporal neocortex of 27 AD and 21 non-demented control brains was examined to assess mRNA levels of APP isoforms (total APP, APP containing the Kunitz protease inhibitor domain [APP-KPI] and APP770) and APP metabolic enzymatic partners (the APP cleaving enzymes beta-secretase [BACE] and presenilin-1 [PS-1], and putative clearance molecules, low-density lipoprotein receptor protein [LRP] and apolipoprotein E [apoE]). Furthermore, we evaluated how changes in APP at the mRNA level affect the amount of Tris buffer extractable APP protein and Abeta40 and 42 peptides in AD and control brains. As assessed by quantitative PCR, APP-KPI (p=0.007), APP770 (p=0.004), PS-1 (p=0.004), LRP (p=0.003), apoE (p=0.0002) and GFAP (p<0.0001) mRNA levels all increased in AD, and there was a shift from APP695 (a neuronal isoform) towards KPI containing isoforms that are present in glia as well. APP-KPI mRNA levels correlated with soluble APPalpha-KPI protein (sAPPalpha-KPI) levels measured by ELISA (tau=0.33, p=0.015 by Kendall's rank correlation); in turn, soluble APPalpha-KPI protein levels positively correlated with Tris-extractable, soluble Abeta40 (p=0.046) and 42 levels (p=0.007). The ratio of soluble APPalpha-KPI protein levels to total APP protein increased in AD, and also correlated with GFAP protein levels in AD. These results suggest that altered transcription of APP in AD is proportionately associated with Abeta peptide, may occur in the context of gliosis, and may contribute to Abeta deposition in sporadic AD.
在21三体综合征以及淀粉样前体蛋白（APP）三倍体的罕见病例中，阿尔茨海默病（AD）的病理变化被认为是APP表达增加的继发结果。我们推测散发性AD可能也与APP或其代谢伙伴的转录变化有关。为解决这一问题，我们检测了27例AD患者和21例非痴呆对照者大脑的颞叶新皮质，以评估APP异构体（总APP、含库尼茨蛋白酶抑制剂结构域的APP [APP-KPI]和APP770）以及APP代谢酶伙伴（APP切割酶β-分泌酶 [BACE]和早老素-1 [PS-1]，以及假定的清除分子，低密度脂蛋白受体蛋白 [LRP]和载脂蛋白E [apoE]）的mRNA水平。此外，我们评估了mRNA水平上APP的变化如何影响AD患者和对照者大脑中三羟甲基氨基甲烷缓冲液可提取的APP蛋白以及β淀粉样蛋白40和42肽的量。通过定量PCR评估，APP-KPI（p = 0.007）、APP770（p = 0.004）、PS-1（p = 0.004）、LRP（p = 0.003）、apoE（p = 0.0002）和胶质纤维酸性蛋白（GFAP，p < 0.0001）的mRNA水平在AD患者中均升高，并且存在从APP695（一种神经元异构体）向同样存在于神经胶质中的含KPI异构体的转变。APP-KPI的mRNA水平与通过酶联免疫吸附测定法（ELISA）测得的可溶性APPα-KPI蛋白（sAPPα-KPI）水平相关（肯德尔等级相关分析，τ = 0.33，p = 0.015）；反过来，可溶性APPα-KPI蛋白水平与三羟甲基氨基甲烷可提取的可溶性β淀粉样蛋白40（p = 0.046）和42水平（p = 0.007）呈正相关。AD患者中可溶性APPα-KPI蛋白水平与总APP蛋白的比值升高，并且也与AD患者中的GFAP蛋白水平相关。这些结果表明，AD中APP转录的改变与β淀粉样肽成比例相关，可能发生在胶质细胞增生的背景下，并且可能导致散发性AD中的β淀粉样蛋白沉积。
