Regulation of cholesterol and sphingomyelin metabolism by amyloid-[beta] and presenilin
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. Hydroxymet...
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| Veröffentlicht in: | Nature cell biology 2005-11, Vol.7 (11), p.1118 |
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| creator | Grimm, Marcus O W Grimm, Heike S Pätzold, Andreas J Zinser, Eva G Halonen, Riikka Duering, Marco Jakob-A. Tschäpe De Strooper, Bart Müller, Ulrike Shen, Jie Hartmann, Tobias |
| description | 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). |
| doi_str_mv | 10.1038/ncb1313 |
| format | Article |
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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. 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| source | Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | Alzheimer's disease Biosynthesis Brain Cholesterol Disease Enzymes Homeostasis Lipids Metabolism Mutation Peptides Physiology Scientific imaging |
| title | Regulation of cholesterol and sphingomyelin metabolism by amyloid-[beta] and presenilin |
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