Differential regulation of basic helix-loop-helix factors Mash1 and Olig2 by β-amyloid accelerates both differentiation and death of cultured neural stem/progenitor cells

Despite increased neurogenic differentiation markers in the hippocampal CA1 in Alzheimer disease, neurons are not replaced in CA1 and the neocortex in the disease. beta-Amyloid (A beta) might cause deterioration of the brain microenvironment supporting neurogenesis and the survival of immature neurons. To test this possibility, we examined whether A beta alters the expression of cell fate determinants in cerebral cortical cultures and in an Alzheimer disease mouse model (PrP-APPSW). Upregulation of Mash1 and down-regulation of Olig2 were found in cerebral cortical cultures treated with A beta-(1-42). Mash1 was expressed in nestin-positive immature cells. The majority of Mash1-positive cells in untreated cortical culture co-expressed Olig2. A beta increased the proportion of Olig2-negative/Mash1-positive cells. A decrease in Olig2+ cells was also observed in the cerebral cortex of adult PrP-APPSW mice. Cotransfection experiments with Mash1 cDNA and Olig2 siRNA revealed that overexpression of Mash1 in neurosphere cells retaining Olig2 expression enhanced neural differentiation but accelerated death of Olig2-depleted cells. Growth factor deprivation, which down-regulated Olig2, accelerated death of Mash1-overexpressing neurosphere cells. We conclude that cooperation between Mash1 and Olig2 is necessary for neural stem/progenitor cells to develop into fully mature neurons and that downregulation of Olig2 by A beta in Mash1-overexpressing cells switches the cell fate to death. Maintaining Olig2 expression in differentiating cells could have therapeutic potential.