NSE promoted the survival of neurons not only in neocortical cultures but also in mesencephalic and spinal cord cultures. Furthermore, NSE showed neuroprotective action on cultured neocortical neurons in a low-oxygen atmosphere.;We show that gamma-enolase-mediated PI3K activation regulates RhoA kinase, a key regulator of actin cytoskeleton organization. Moreover, the inhibition of RhoA downstream effector ROCK (Rho-associated kinase) results in enhanced gamma-enolase-induced neurite outgrowth, accompanied by actin polymerization and its redistribution to growth cones. Our results show that gamma-enolase controls neuronal survival, differentiation and neurite regeneration by activating the PI3K/Akt and MAPK/ERK signalling pathways, resulting in downstream regulation of the molecular and cellular processes of cytoskeleton reorganization and cell remodelling, activation of transcriptional factors and regulation of the cell cycle.; The upregulation of c-enolase in microglial cells in response to amyloid-b peptide (Ab) was confirmed in mouse microglial cell line EOC 13.31 and primary microglia and medium enriched with gamma-enolase proved to be neuroprotective against Ab toxicity, however, the effect was reversed by cathepsin X proteolytic activity. These results demonstrate an upregulation of gamma-enolase in microglia cells surrounding amyloid plaques in Tg2576 transgenic mice and demonstrate its neuroprotective role in amyloid-b-related neurodegeneration.