Activation barriers to structural transition determine deposition rates of Alzheimer's disease a beta amyloid.
Brain amyloid composed of the approximately 40-amino-acid human beta-amyloid peptide A beta is integral to Alzheimer's disease pathology. To probe the importance of a conformational transition in Abeta during amyloid growth, we synthesized and examined the solution conformation and amyloid deposition activity of A beta congeners designed to have similar solution structures but to vary substantially in their barriers to conformational transition. Although all these peptides adopt similar solution conformations, a covalently restricted Abeta congener designed to have a very high barrier to conformational rearrangement was inactive, while a peptide designed to have a reduced barrier to conformational transition displayed an enhanced deposition rate relative to wild-type A beta. The hyperactive peptide, which is linked to a heritable A beta amyloidosis characterized by massive amyloid deposition at an early age, displayed a reduced activation barrier to deposition consistent with a larger difference in activation entropy than in activation enthalpy relative to wild-type A beta. These results suggest that in Alzheimer's disease, as in the prion diseases, a conformational transition in the depositing peptide is essential for the conversion of soluble monomer to insoluble amyloid, and alterations in the activation barrier to this transition affect amyloidogenicity and directly contribute to human disease.
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267, USA.
W P
WP
Esler
A M
AM
Felix
E R
ER
Stimson
M J
MJ
Lachenmann
J R
JR
Ghilardi
Y A
YA
Lu
H V
HV
Vinters
P W
PW
Mantyh
J P
JP
Lee
J E
JE
Maggio
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism*; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D058225:Plaque, Amyloid / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D013696:Temperature; D013816:Thermodynamics
D016229:Amyloid beta-Peptides; D010455:Peptides