Enhancement of long-term depression by soluble amyloid β protein in rat hippocampus is mediated by metabotropic glutamate receptor and involves activation of p38MAPK, STEP and caspase-3

Neuroscience. 2013 Dec 3;253:435-43. doi: 10.1016/j.neuroscience.2013.08.054. Epub 2013 Sep 5.


It is reported that the amyloid-β protein (Aβ)-induced impairments in synaptic plasticity coincide with memory decline and dementia. Although Aβ-induced inhibition of hippocampal long-term potentiation has been intensively investigated, the underlying mechanism of Aβ-enhanced long-term depression (LTD) is not clear. Here, we report that acute exposure of rat hippocampal slices to soluble Aβ-enhanced LTD induced by weak low-frequency stimulation (wLFS; 1Hz for 3 min, 180 pulses) in granule cells of the dentate gyrus. Application of LY341495 (a non-selective Group I/II metrabotropic glumate receptor (mGluR) antagonist) completely blocked Aβ-enhanced LTD, whereas D-AP5 (a not selective N-methyl-d-aspartate receptor (NMDAR) antagonist) had no effect on Aβ-enhanced LTD compared with controls. In addition, Aβ-enhanced LTD was occluded by pre-application of 3,5-dihydroxyphenylglycine, a Group1 mGluR (mGluR1/5) agonist, suggesting Aβ-enhanced LTD depends on mGluR1/5 but not NMDAR. We also report here that p38 mitogen-activated protein kinase (p38MAPK) inhibitor SB203580 and postsynaptic protein tyrosine phosphatase inhibitors phenylarsine oxide and sodium orthovanadate prevented the facilitatory effect of Aβ on LTD. Application of striatal-enriched protein tyrosine phosphatase (STEP) activator MG132 facilitated induction of LTD by wLFS, but did not block following Aβ-enhanced LTD induced by another wLFS. On the other hand, Aβ-enhanced LTD blocked following MG132-LTD by wLFS, suggesting Aβ-enhanced hippocampal LTD involves STEP activation. Application of either non-selective caspase inhibitor Z-VAD-FMK or caspase-3 selective inhibitor Z-DEVD-FMK prevented Aβ-enhanced LTD. However, neither the tumor necrosis factor-α converting enzyme inhibitor TAPI-2 nor the mammalian target of rapamycin inhibitor rapamycin prevented the enhancement of Aβ on LTD. Therefore, we conclude that soluble Aβ enhances LTD in the hippocampal dentate gyrus region, and the facilitatory effect of Aβ on LTD involves mGluR1/5, p38MAPK, STEP and caspase-3 activation.

Keywords: 3,5-dihydroxyphenylglycine; AD; AMPAR; Alzheimer’s disease; Aβ; DHPG; EPSP; LTD; LTP; N-methyl-d-aspartate receptor; NMDAR; NPR; PAO; PTP; SO; STEP; TACE; a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; amyloid beta protein; amyloid-β protein; excitatory postsynaptic potential; fEPSPs; field excitatory postsynaptic potentials; hippocampus; long-term depression; long-term potentiation; mGluRs; mTOR; mammalian target of Rapamycin; metabotropic glumate receptor; metrabotropic glumate receptors; neuronal pentraxin receptor; p38 mitogen-activated protein kinase; p38MAPK; phenylarsine oxide; postsynaptic protein tyrosine phosphatase; sLFS; sodium orthovanadate; striatal-enriched protein tyrosine phosphatase; strong low-frequency stimulation; synaptic plasticity; tumor necrosis factor-α converting enzyme; wLFS; weak low-frequency stimulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • Amino Acids / pharmacology
  • Amyloid beta-Peptides / pharmacology*
  • Animals
  • Caspase 3 / metabolism*
  • Electric Stimulation
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Hippocampus / drug effects*
  • Immunosuppressive Agents / pharmacology
  • In Vitro Techniques
  • Long-Term Synaptic Depression / drug effects*
  • Male
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Patch-Clamp Techniques
  • Peptide Fragments / pharmacology*
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
  • Rats
  • Rats, Wistar
  • Receptors, Metabotropic Glutamate / metabolism*
  • Sirolimus / pharmacology
  • Xanthenes / pharmacology
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Amino Acids
  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Immunosuppressive Agents
  • LY 341495
  • Peptide Fragments
  • Receptors, Metabotropic Glutamate
  • Xanthenes
  • amyloid beta-protein (1-42)
  • Methoxyhydroxyphenylglycol
  • 2-Amino-5-phosphonovalerate
  • p38 Mitogen-Activated Protein Kinases
  • Protein Tyrosine Phosphatases, Non-Receptor
  • Ptpn5 protein, rat
  • Caspase 3
  • 3,4-dihydroxyphenylglycol
  • Sirolimus