C-Terminal Peptide of γ-Enolase Impairs Amyloid-β-Induced Apoptosis Through p75NTR Signaling

gamma-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-beta-peptide (A beta)-induced neurotoxicity in rat pheochromocytoma PC12 cells. A beta-induced toxicity was abolished in the presence of the active C-terminal peptide of gamma-enolase (gamma-Eno) as measured by cell viability, lactate dehydrogenase release, sub-G1 cell population, intracellular reactive oxygen species, mitochondrial functions and apoptotic morphology. gamma-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 A beta increased surface expression of p75 neurotrophin receptor (p75(NTR)), and the increase was abolished in the presence of gamma-Eno peptide. Further, pretreatment with gamma-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, A beta triggered gamma-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 A beta peptide. Our results indicate the possible use of gamma-enolase C-terminal peptide for treating or preventing Alzheimer's disease.