Author:

Keywords:

Amyloid beta-Protein, Amyloid beta-Protein Precursor, Animals, COS Cells, Cells, Cultured, Cercopithecus aethiops, Cholesterol, Endopeptidases, Gene Expression Regulation, Humans, Lipid Metabolism, Membrane Proteins, Mice, Peptide Fragments, Research Support, Non-U.S. Gov't, Sphingomyelin Phosphodiesterase, Sphingomyelins, Science & Technology, Life Sciences & Biomedicine, Cell Biology, GAMMA-SECRETASE ACTIVITY, ALZHEIMERS-DISEASE, PRECURSOR PROTEIN, CEREBROSPINAL-FLUID, IN-VIVO, CELLS, EXPRESSION, PEPTIDES, STRESS, SIMVASTATIN, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Chlorocebus aethiops, Presenilin-1, Presenilin-2, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 3101 Biochemistry and cell biology

Abstract:

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).