Alzheimer amyloid beta-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus

Neurobiol Learn Mem. 2002 May;77(3):354-71. doi: 10.1006/nlme.2001.4034.

Abstract

The perforant path projecting from the entorhinal cortex to the hippocampal dentate gyrus is a particularly vulnerable target to the early deposition of amyloid beta (Abeta) peptides in Alzheimer's brain. The authors previously showed that brief applications of Abeta at subneurotoxic concentrations suppressed the early-phase long-term potentiation (E-LTP) in rat dentate gyrus. The current study further examines the effect of Abeta on the late-phase LTP (L-LTP) in this area. Using multiple high-frequency stimulus trains, a stable L-LTP lasting for at least 3 h was induced in the medial perforant path of rat hippocampal slices. Bath application of Abeta(1-42) (0.2-1.0 microM) during the induction trains attenuated both the initial and late stages of L-LTP. On the other hand, Abeta(1-42) perfusion within the first hour following the induction primarily impaired the late stage of L-LTP, which resembled the action of the protein synthesis inhibitor emetine. Blockade of calcineurin activity with FK506 or cyclosporin A completely prevented Abeta-induced L-LTP deficits. These results suggest that Abeta(1-42) impaired both the induction and maintenance phase of dentate L-LTP through calcineurin-dependent mechanisms. In the concentration range effective for inhibiting L-LTP, Abeta(1-42) also reduced the amplitude of NMDA receptor-mediated synaptic currents in dentate granule cells via a postsynaptic mechanism. In addition, concurrent applications of Abeta(1-42) with the protein synthesis inhibitor caused no additive reduction of L-LTP, indicating a common mechanism underlying the action of both. Thus, inhibition of NMDA receptor channels and disruption of protein synthesis were two possible mechanisms contributing to Abeta-induced L-LTP impairment.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / adverse effects*
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Animals
  • Calcineurin / metabolism*
  • Cyclosporine / adverse effects
  • Dentate Gyrus / metabolism*
  • Disease Models, Animal
  • Hippocampus / metabolism*
  • Immunosuppressive Agents / adverse effects
  • Long-Term Potentiation
  • Male
  • N-Methylaspartate / metabolism
  • Phospholipids / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Tacrolimus / adverse effects

Substances

  • Amyloid beta-Peptides
  • Immunosuppressive Agents
  • Phospholipids
  • N-Methylaspartate
  • Cyclosporine
  • Calcineurin
  • Tacrolimus