Journal
EUROPEAN JOURNAL OF NEUROSCIENCE
Volume 19, Issue 10, Pages 2839-2846Publisher
WILEY
DOI: 10.1111/j.1460-9568.2004.03389.x
Keywords
CA1 area; synaptic plasticity; Alzheimer's disease; peptide aggregation; rat
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Funding
- NIA NIH HHS [AG06173] Funding Source: Medline
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Mutations in the amyloid precursor protein that result in substitutions of glutamic acid at residue 22 of the amyloid beta protein (Abeta) 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 Abeta(1-40) peptides were examined in the CA1 area of urethane-anaesthetized rats. Both mutant peptides were approximate to 100-fold more potent than wild-type Abeta at inhibiting LTP induced by high-frequency stimulation when solutions of Abeta 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 Abeta(1-40)G22 and Abeta(1-40)Q22. A soluble fraction of Abeta(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 Abeta may represent the primary mediator of Abeta-related cognitive deficits, particularly early in the disease. In contrast, nonfibrillar soluble Abeta(1-40)Q22 supernatant solution was approximate to 10-fold less potent at inhibiting LTP than Abeta(1-40)G22, a finding consistent with fibrillar Abeta contributing to the inhibition of LTP by the Dutch peptide.
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