Expression of APP pathway mRNAs and proteins in Alzheimer's disease
Expression of APP pathway mRNAs and proteins in Alzheimer's disease
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DOI：
10.1016/j.brainres.2007.05.050
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发表时间：
2007-08-03
期刊：
影响因子：
2.9
通讯作者：
Hyman, Bradley T.
中科院分区：
文献类型：
--
作者：
Matsui, Toshifumi;Ingelsson, Martin;Hyman, Bradley T.
在三体21和罕见的情况下，三倍的淀粉样前体蛋白（APP）阿尔茨海默氏病（AD）的病理变化被认为是继发于APP的表达增加。我们假设，散发性AD也可能与APP或其代谢伙伴的转录变化。为了解决这一问题，对27例AD和21例非痴呆对照大脑的颞叶新皮层进行了检查，以评估APP亚型的mRNA水平（总APP、含Kunitz蛋白酶抑制剂结构域的APP [APP-KPI]和APP 770）和APP代谢酶伴侣（APP裂解酶β-分泌酶[BACE]和早老素-1 [PS- 1]，以及推定的清除分子，低密度脂蛋白受体蛋白[LRP]和载脂蛋白E [apoE]）。此外，我们评估了APP在mRNA水平上的变化如何影响AD和对照脑中Tris缓冲液可提取的APP蛋白和A β 40和42肽的量。通过定量PCR评估，APP-KPI（p=0.007），APP 770（p=0.004），PS-1（p = 0.004），LRP（p = 0.003），apoE（p = 0.0002）和GFAP（p < 0.0001）mRNA水平在AD中均增加，并且存在从APP 695（神经元同种型）向含有同样存在于神经胶质中的同种型的KPI的转变。APP-KPI mRNA水平与通过ELISA测量的可溶性APPa-KPI蛋白（sAPPa-KPI）水平相关（通过Kendall等级相关性，T= 0.33，p = 0.015）;反过来，可溶性APPa-KPI蛋白水平与Tris可提取的可溶性A β 40（p=0.046）和42水平正相关（p=0.007）。可溶性APP α-KPI蛋白水平占总APP蛋白的比例在AD中增加，并且还与AD中的GFAP蛋白水平相关。这些结果表明，在AD中APP的转录改变与A β肽成比例相关，可能发生在神经胶质增生的背景下，并可能有助于散发性AD中的A β沉积。
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 A beta 40 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 APP alpha -KPI protein (sAPP alpha -KPI) levels measured by ELISA (T= 0.33, p = 0.015 by Kendall's rank correlation); in turn, soluble APP alpha-KPI protein levels positively correlated with Tris -extractable, soluble A beta 40 (p=0.046) and 42 levels (p=0.007). The ratio of soluble APP alpha-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 A beta peptide, may occur in the context of gliosis, and may contribute to A beta deposition in sporadic AD.