Controlling polymerization of beta-amyloid and prion-derived peptides with synthetic small molecule ligands.
The Alzheimer beta-amyloid peptide (Abeta) and a fragment of the prion protein have the capacity of forming amyloid-like fibrils when incubated under physiological conditions in vitro. Here we show that a small amyloid ligand, RO-47-1816/001, enhances this process severalfold by binding to amyloid molecules and apparently promote formation of the peptide-to-peptide bonds that join the monomers of the amyloid fibrils. This effect could be antagonized by other ligands, including analogues of RO-47-1816/001, as well as the structurally unrelated ligand Congo red. Analogues of RO-47-1816/001 with low affinity for amyloid did not display any antagonistic effect. In conclusion, these data suggest that synthetic molecules, and possibly also small natural substances present in the brain, may act in a chaperone-like fashion, promoting Abeta polymerization and growth of amyloid fibrils in vitro and possibly also in vivo. Furthermore, we demonstrate that small organic molecules can be used to inhibit the action of amyloid-enhancing compounds.
Kuner
P
P
F. Hoffmann-La Roche AG, Pharma Division, Preclinical Research, CH-4070 Basel, Switzerland.
Bohrmann
B
B
Tjernberg
L O
LO
Näslund
J
J
Huber
G
G
Celenk
S
S
Grüninger-Leitch
F
F
Richards
J G
JG
Jakob-Roetne
R
R
Kemp
J A
JA
Nordstedt
C
C
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000648:ultrastructure; D015153:Blotting, Western; D004396:Coloring Agents / Q000494:pharmacology; D003224:Congo Red / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008024:Ligands; D010455:Peptides / Q000378:metabolism*; D011328:Prions / Q000378:metabolism*; D011485:Protein Binding; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D012709:Serum Albumin / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013997:Time Factors
D016229:Amyloid beta-Peptides; D004396:Coloring Agents; D008024:Ligands; D010455:Peptides; D011328:Prions; D011728:Pyridones; C404102:RO-47-1816-001; D012709:Serum Albumin; D003224:Congo Red