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Keywords:

  • CA1 area;
  • synaptic plasticity;
  • Alzheimer's disease;
  • peptide aggregation;
  • rat

Abstract

Mutations in the amyloid precursor protein that result in substitutions of glutamic acid at residue 22 of the amyloid β protein (Aβ) 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 Aβ(1–40) peptides were examined in the CA1 area of urethane-anaesthetized rats. Both mutant peptides were ≈ 100-fold more potent than wild-type Aβ at inhibiting LTP induced by high-frequency stimulation when solutions of Aβ 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 Aβ(1–40)G22 and Aβ(1–40)Q22. A soluble fraction of Aβ(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 Aβ may represent the primary mediator of Aβ-related cognitive deficits, particularly early in the disease. In contrast, nonfibrillar soluble Aβ(1–40)Q22 supernatant solution was ≈ 10-fold less potent at inhibiting LTP than Aβ(1–40)G22, a finding consistent with fibrillar Aβ contributing to the inhibition of LTP by the Dutch peptide.