The memory enhancing effect of the APP-derived tripeptide Ac-rER is mediated through CRMP2.
The diasteromeric (D/L) form of the acetylated tripeptide rER (NH2-D-arg-L-glu-D-arg-COOH), derived from the external domain of amyloid precursor protein, protects against amyloid-β induced memory loss for a passive avoidance task in young chicks and enhances retention for a weak version of the task when injected peripherally up to 12 h prior to training. The tripeptide readily crosses the blood-brain barrier, binds to receptor sites in the brain and is without adverse effects on general behaviour. The mechanisms of its action are unknown, as are its target molecules/pathways. Here, we report the binding partners for Ac-rER are collapsin response mediator protein 2 (CRMP2), syntaxin binding protein 1 and heat shock protein 70. Behavioural studies of the effects of Ac-rER on memory retention confirmed that the effect of Ac-rER is mediated via CRMP2, as anti-CRMP2 antibodies if injected intracranially 30 min pre-training, induced amnesia for the passive avoidance task. However, Ac-rER, if injected prior to the anti-CRMP2, rescues the memory deficits induced by anti-CRMP2 antibodies. As CRMP2 is placed at the junction of many different cellular processes during brain development and in adult neuronal plasticity as well as being implicated in Alzheimer's disease, this strengthens the claim that Ac-rER may be a potential therapeutic agent in Alzheimer's disease, although its precise mode of action remains to be elucidated.
Department of Life Sciences, The Open University, Milton Keynes, UK. r.mileusnic@open.ac.uk
Radmila
R
Mileusnic
Steven P R
SP
Rose
D000647:Amnesia / Q000139:chemically induced / Q000517:prevention & control; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D019921:Biotinylation; D015153:Blotting, Western; D001923:Brain Chemistry; D002645:Chickens; D003216:Conditioning, Operant / Q000187:drug effects; D003287:Contrast Media; D004591:Electrophoresis, Polyacrylamide Gel; D019793:Fluorescein; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007123:Immunoelectrophoresis, Two-Dimensional; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008568:Memory / Q000187:drug effects; D051938:Munc18 Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology*; D011485:Protein Binding; D040901:Proteomics
D016564:Amyloid beta-Protein Precursor; D003287:Contrast Media; D050883:HSC70 Heat-Shock Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; C561049:acetyl-arginyl-glutamyl-arginine; C095114:collapsin response mediator protein-2; D019793:Fluorescein