Grimm Marcus O W, Grimm Heike S, Pätzold Andreas J, Zinser Eva G, Halonen Riikka, Duering Marco, Tschäpe Jakob A, De Strooper Bart, Müller Ulrike, Shen Jie, Hartmann Tobias
Centre for Molecular Biology Heidelberg, INF 282, D-69120 Heidelberg, Germany.
Nat Cell Biol. 2005 Nov;7(11):1118-23. doi: 10.1038/ncb1313.
Amyloid beta peptide (Abeta) has a key role in the pathological process of Alzheimer's disease (AD), but the physiological function of Abeta and of the amyloid precursor protein (APP) is unknown. Recently, it was shown that APP processing is sensitive to cholesterol and other lipids. Hydroxymethylglutaryl-CoA reductase (HMGR) and sphingomyelinases (SMases) are the main enzymes that regulate cholesterol biosynthesis and sphingomyelin (SM) levels, respectively. We show that control of cholesterol and SM metabolism involves APP processing. Abeta42 directly activates neutral SMase and downregulates SM levels, whereas Abeta40 reduces cholesterol de novo synthesis by inhibition of HMGR activity. This process strictly depends on gamma-secretase activity. In line with altered Abeta40/42 generation, pathological presenilin mutations result in increased cholesterol and decreased SM levels. Our results demonstrate a biological function for APP processing and also a functional basis for the link that has been observed between lipids and Alzheimer's disease (AD).
β淀粉样肽（Aβ）在阿尔茨海默病（AD）的病理过程中起关键作用，但Aβ和淀粉样前体蛋白（APP）的生理功能尚不清楚。最近的研究表明，APP的加工过程对胆固醇和其他脂质敏感。羟甲基戊二酰辅酶A还原酶（HMGR）和鞘磷脂酶（SMases）分别是调节胆固醇生物合成和鞘磷脂（SM）水平的主要酶。我们发现，胆固醇和SM代谢的调控涉及APP的加工过程。Aβ42直接激活中性SMase并下调SM水平，而Aβ40通过抑制HMGR活性减少胆固醇的从头合成。这个过程严格依赖于γ-分泌酶的活性。与Aβ40/42生成的改变一致，病理性早老素突变导致胆固醇增加和SM水平降低。我们的结果证明了APP加工过程的生物学功能，也为脂质与阿尔茨海默病（AD）之间已观察到的联系提供了功能基础。
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