(I) Pharmacological profiling of a novel modulator of the α7 nicotinic receptor: Blockade of a toxic acetylcholinesterase-derived peptide increased in Alzheimer brains

Neuropharmacology. 2016 Jun;105:487-499. doi: 10.1016/j.neuropharm.2016.02.006. Epub 2016 Feb 8.

Abstract

The primary cause of Alzheimer's disease is unlikely to be the much studied markers amyloid beta or tau. Their widespread distribution throughout the brain does not account for the specific identity and deep subcortical location of the primarily vulnerable neurons. Moreover an unusual and intriguing feature of these neurons is that, despite their diverse transmitters, they all contain acetylcholinesterase. Here we show for the first time that (1) a peptide derived from acetylcholinesterase, with independent trophic functions that turn toxic in maturity, is significantly raised in the Alzheimer midbrain and cerebrospinal fluid; (2) a synthetic version of this peptide enhances calcium influx and eventual production of amyloid beta and tau phosphorylation via an allosteric site on the α7 nicotinic receptor; (3) a synthetic cyclic version of this peptide is neuroprotective against the toxicity not only of its linear counterpart but also of amyloid beta, thereby opening up the prospect of a novel therapeutic approach.

Keywords: Acetylcholinesterase C-terminal peptide; Alzheimer's disease; Cyclic peptide; Pheochromocytoma cells 12; α7nicotinic receptor.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Allosteric Site
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Biomarkers / metabolism
  • Brain / drug effects
  • Brain / metabolism*
  • Cell Survival / drug effects
  • Cholinesterase Inhibitors / pharmacology
  • Galantamine / pharmacology
  • Humans
  • Hydrogen Peroxide / metabolism
  • Neuroprotective Agents / pharmacology
  • PC12 Cells
  • Peptide Fragments / metabolism*
  • Peptide Fragments / pharmacology
  • Peptides, Cyclic / metabolism
  • Peptides, Cyclic / pharmacology
  • Rats
  • Tissue Culture Techniques
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism*
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • Biomarkers
  • Cholinesterase Inhibitors
  • MAPT protein, human
  • NBP14 peptide
  • Neuroprotective Agents
  • Peptide Fragments
  • Peptides, Cyclic
  • alpha7 Nicotinic Acetylcholine Receptor
  • amyloid beta-peptide (1-14)
  • amyloid beta-peptide (1-30)
  • tau Proteins
  • Galantamine
  • Hydrogen Peroxide
  • Acetylcholinesterase