1H NMR of A beta amyloid peptide congeners in water solution. Conformational changes correlate with plaque competence.
To begin to examine the structural basis for the deposition of soluble A beta amyloid peptide onto senile plaques in Alzheimer's disease, we have prepared A beta congeners and measured their activity in an in vitro plaque growth assay. The N-terminal fragment, A beta (1-28)-OH, was inactive at all pH values tested. While the central fragment, A beta (10-35)-NH2, and the full length peptide, A beta (1-40)-OH, were inactive below pH 4, both were active (plaque competent) between pH 5 and 9. The active and inactive fragments were studied by nuclear magnetic resonance spectroscopy in water at submillimolar concentrations at pH 2.1 and 5.6. Changes in chemical shifts, coupling constants, and nuclear Overhauser enhancements indicate a pH dependent folding transition in A beta (10-35)-NH2 as it becomes active. The conformation of the active fragment is not helical, and preliminary data indicate the presence of several turns and at least two short strands. In contrast, the inactive fragment A beta (1-28)-OH did not undergo a similar folding transition. Earlier nuclear magnetic resonance studies of amyloid peptides in fluorinated alcohols or detergent micelles at low pH described a helical conformation and proposed a helix to sheet transition in plaque formation; the present study demonstrates that no such conformations are present in water under conditions where the peptides can adhere to authentic amyloid plaques.
Lee
J P
JP
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Stimson
E R
ER
Ghilardi
J R
JR
Mantyh
P W
PW
Lu
Y A
YA
Felix
A M
AM
Llanos
W
W
Behbin
A
A
Cummings
M
M
Van Criekinge
M
M
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000502:physiology*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006859:Hydrogen; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000502:physiology*; D012996:Solutions; D013329:Structure-Activity Relationship; D014867:Water
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012996:Solutions; C075222:amyloid beta-protein (1-42); D014867:Water; D006859:Hydrogen