title: C-terminal peptide of γ-enolase impairs amyloid-β-induced apoptosis through p75(NTR) signaling.
abstract: γ-Enolase acts as a neurotrophic-like factor promoting growth, differentiation, survival and regeneration of neurons. It is shown in this study to exert a protective effect against amyloid-β-peptide (Aβ)-induced neurotoxicity in rat pheochromocytoma PC12 cells. Aβ-induced toxicity was abolished in the presence of the active C-terminal peptide of γ-enolase (γ-Eno) as measured by cell viability, lactate dehydrogenase release, sub-G1 cell population, intracellular reactive oxygen species, mitochondrial functions and apoptotic morphology. γ-Eno caused downregulation of the pro-apoptotic protein Bax and upregulation of the anti-apoptotic protein Bcl-2, as well as reduced caspase-3 activation. Exposure to Aβ increased surface expression of p75 neurotrophin receptor (p75(NTR)), and the increase was abolished in the presence of γ-Eno peptide. Further, pretreatment with γ-Eno suppressed the activation of mitogen-activated protein kinases p38 and Jun-N-terminal kinase, which are p75(NTR) downstream effectors in apoptotic signaling. Moreover, Aβ triggered γ-enolase co-immunoprecipitation with p75(NTR) as well as their strong association in the perimembrane region as shown by confocal microscopy, which further supports the interaction between these two proteins in cells insulted by Aβ peptide. Our results indicate the possible use of γ-enolase C-terminal peptide for treating or preventing Alzheimer's disease.
authors.affiliation: Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000, Ljubljana, Slovenia. anja.pislar@ffa.uni-lj.si
authors.forename: Anja Hafner
authors.initials: AH
authors.lastname: Pišlar
authors.forename: Janko
authors.initials: J
authors.lastname: Kos
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008959:Models, Neurological; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity*; D010751:Phosphopyruvate Hydratase / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; C494828:Bax protein, rat; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D051028:bcl-2-Associated X Protein; C068313:Ngfr protein, rat; C505410:Casp3 protein, rat; D053148:Caspase 3; D010751:Phosphopyruvate Hydratase