Soluble Arctic amyloid beta protein inhibits hippocampal long-term potentiation in vivo.
Mutations in the amyloid precursor protein that result in substitutions of glutamic acid at residue 22 of the amyloid beta protein (A beta) with glutamine (Q22, Dutch) or glycine (G22, Arctic) cause aggressive familial neurological diseases characterized by cerebrovascular haemorrhages or Alzheimer's-type dementia, respectively. The present study compared the ability of these peptides to block long-term potentiation (LTP) of glutamatergic transmission in the hippocampus in vivo. The effects of intracerebroventricular injection of wild-type, Q22 and G22 A beta(1-40) peptides were examined in the CA1 area of urethane-anaesthetized rats. Both mutant peptides were approximately 100-fold more potent than wild-type A beta at inhibiting LTP induced by high-frequency stimulation when solutions of A beta were freshly prepared. Fibrillar material, as determined by electron microscopy, was obvious in all these peptide solutions and exhibited appreciable Congo Red binding, particularly for A beta(1-40)G22 and A beta(1-40)Q22. A soluble fraction of A beta(1-40)G22, obtained following high-speed centrifugation, retained full activity of the peptide solution to inhibit LTP, providing strong evidence that in the case of the Arctic disease a soluble nonfibrillar form of A beta may represent the primary mediator of A beta-related cognitive deficits, particularly early in the disease. In contrast, nonfibrillar soluble A beta(1-40)Q22 supernatant solution was approximately 10-fold less potent at inhibiting LTP than A beta(1-40)G22, a finding consistent with fibrillar A beta contributing to the inhibition of LTP by the Dutch peptide.
Klyubin
Igor
I
Trinity College Institute of Neuroscience, and Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland.
Walsh
Dominic M
DM
Cullen
William K
WK
Fadeeva
Julia V
JV
Anwyl
Roger
R
Selkoe
Dennis J
DJ
Rowan
Michael J
MJ
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D003224:Congo Red; D004305:Dose-Response Relationship, Drug; D004567:Electrodes, Implanted; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000235:genetics; D005998:Glycine / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D009154:Mutation; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid; D003224:Congo Red; D005998:Glycine