The interaction of beta-amyloid protein with cellular membranes stimulates its own production.
Gradual changes in steady-state levels of beta amyloid peptides (Abeta) in brain are considered an initial step in the amyloid cascade hypothesis of Alzheimer's disease. Abeta is a product of the secretase cleavage of amyloid precursor protein (APP). There is evidence that the membrane lipid environment may modulate secretase activity and alters its function. Cleavage of APP strongly depends on membrane properties. Since Abeta perturbs cell membrane fluidity, the cell membrane may be the location where the neurotoxic cascade of Abeta is initiated. Therefore, we tested effects of oligomeric Abeta on membrane fluidity of whole living cells, the impact of exogenous and cellular Abeta on the processing of APP and the role of GM-1 ganglioside. We present evidence that oligoAbeta((1-40)) stimulates the amyloidogenic processing of APP by reducing membrane fluidity and complexing with GM-1 ganglioside. This dynamic action of Abeta may start a vicious circle, where endogenous Abeta stimulates its own production. Based on our novel findings, we propose that oligoAbeta((1-40)) accelerates the proteolytic cleavage of APP by decreasing membrane fluidity.
Department of Pharmacology, Goethe-University of Frankfurt am Main, Campus Riedberg, Biocenter Geb. N260, R.1.09, Max-von-Laue Str. 9, D-60438 Frankfurt, Germany.
Imke
I
Peters
Urule
U
Igbavboa
Tanja
T
Schütt
Schamim
S
Haidari
Ulrike
U
Hartig
Ximena
X
Rosello
Steffi
S
Böttner
Ekaterini
E
Copanaki
Thomas
T
Deller
Donat
D
Kögel
W Gibson
WG
Wood
Walter E
WE
Müller
Gunter P
GP
Eckert
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D055592:Biophysical Phenomena; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D005677:G(M1) Ganglioside / Q000378:metabolism; D006801:Humans; D008560:Membrane Fluidity; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D020836:Protein Structure, Quaternary
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008563:Membrane Lipids; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005677:G(M1) Ganglioside; D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases