Alzheimer's disease amyloid propagation by a template-dependent dock-lock mechanism.
Amyloid plaques composed of the peptide Abeta are an integral part of Alzheimer's disease (AD) pathogenesis. We have modeled the process of amyloid plaque growth by monitoring the deposition of soluble Abeta onto amyloid in AD brain tissue or synthetic amyloid fibrils and show that it is mediated by two distinct kinetic processes. In the first phase, "dock", Abeta addition to the amyloid template is fully reversible (dissociation t(1/2) approximately 10 min), while in the second phase, "lock", the deposited peptide becomes irreversibly associated (dissociation t(1/2) >> 1000 min) with the template in a time-dependent manner. The most recently deposited peptide dissociates first while Abeta previously deposited becomes irreversibly "locked" onto the template. Thus, the transition from monomer to neurotoxic amyloid is mediated by interaction with the template, a mechanism that has also been proposed for the prion diseases. Interestingly, two Abeta peptides bearing primary sequence alterations implicated in heritable Abeta amyloidoses displayed faster lock-phase kinetics than wild-type Abeta. Inhibiting the initial weak docking interaction between depositing Abeta and the template is a viable therapeutic target to prevent the critical conformational transition in the conversion of Abeta((solution)) to Abeta((amyloid)) and thus prevent stable amyloid accumulation. While thermodynamics suggest that inhibiting amyloid assembly would be difficult, the present study illustrates that the protein misfolding diseases are kinetically vulnerable to intervention.
Esler
W P
WP
Department of Pharmacology & Cell Biophysics, University of Cincinnati College of Medicine, Ohio 45267, USA.
Stimson
E R
ER
Jennings
J M
JM
Vinters
H V
HV
Ghilardi
J R
JR
Lee
J P
JP
Mantyh
P W
PW
Maggio
J E
JE
D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000686:Amyloidosis / Q000473:pathology*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000473:pathology; D011487:Protein Conformation; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)