A novel action of alzheimer's amyloid beta-protein (Abeta): oligomeric Abeta promotes lipid release.
Interactions between amyloid beta-protein (Abeta) and lipids have been suggested to play important roles in the pathogenesis of Alzheimer's disease. However, the molecular mechanism underlying these interactions has not been fully understood. We examined the effect of Abeta on lipid metabolism in cultured neurons and astrocytes and found that oligomeric Abeta, but not monomeric or fibrillar Abeta, promoted lipid release from both types of cells in a dose- and time-dependent manner. The main components of lipids released after the addition of Abeta were cholesterol, phospholipids, and monosialoganglioside (GM1). Density-gradient and electron microscopic analyses of the conditioned media demonstrated that these Abeta and lipids formed particles and were recovered from the fractions at densities of approximately 1.08-1.18 g/ml, which were similar to those of high-density lipoprotein (HDL) generated by apolipoproteins. The lipid release mediated by Abeta was abolished by concomitant treatment with Congo red and the PKC inhibitor, H7, whereas it was not inhibited with N-acetyl-l-cysteine. These Abeta-lipid particles were not internalized into neurons, whereas HDL-like particles produced by apolipoprotein E were internalized. Our findings indicate that oligomeric Abeta promotes lipid release from neuronal membrane, which may lead to the disruption of neuronal lipid homeostasis and the loss of neuronal function.
Michikawa
M
M
Department of Dementia Research, National Institute for Longevity Sciences, Obu, Aichi 474-8522, Japan. michi@nils.go.jp
Gong
J S
JS
Fan
Q W
QW
Sawamura
N
N
Yanagisawa
K
K
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002499:Centrifugation, Density Gradient; D002784:Cholesterol / Q000032:analysis / Q000378:metabolism; D003224:Congo Red / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D050356:Lipid Metabolism; D008055:Lipids / Q000032:analysis / Q000493:pharmacokinetics; D046911:Macromolecular Substances; D008854:Microscopy, Electron; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D010713:Phosphatidylcholines / Q000032:analysis / Q000378:metabolism; D011233:Precipitin Tests; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D013997:Time Factors
D016229:Amyloid beta-Peptides; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D008055:Lipids; D046911:Macromolecular Substances; D010446:Peptide Fragments; D010713:Phosphatidylcholines; C078592:amyloid beta-protein (1-40); D003224:Congo Red; D002784:Cholesterol; D011493:Protein Kinase C