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. 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).
Grimm
Marcus O W
MO
Centre for Molecular Biology Heidelberg, INF 282, D-69120 Heidelberg, Germany.
Grimm
Heike S
HS
Pätzold
Andreas J
AJ
Zinser
Eva G
EG
Halonen
Riikka
R
Duering
Marco
M
Tschäpe
Jakob A
JA
De Strooper
Bart
B
Müller
Ulrike
U
Shen
Jie
J
Hartmann
Tobias
T
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D050356:Lipid Metabolism; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology; D051379:Mice; D010446:Peptide Fragments / Q000032:analysis* / Q000378:metabolism; D053764:Presenilin-1; D053766:Presenilin-2; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; D013109:Sphingomyelins; C444321:amyloid beta-protein (1-34); D002784:Cholesterol; D013108:Sphingomyelin Phosphodiesterase; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse