Differential regulation of basic helix-loop-helix factors Mash1 and Olig2 by beta-amyloid accelerates both differentiation and death of cultured neural stem/progenitor cells - PubMed (original) (raw)

. 2007 Jul 6;282(27):19700-9.

doi: 10.1074/jbc.M703099200. Epub 2007 May 8.

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

Yoko Uchida et al. J Biol Chem. 2007.

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Abstract

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 (Abeta) might cause deterioration of the brain microenvironment supporting neurogenesis and the survival of immature neurons. To test this possibility, we examined whether Abeta alters the expression of cell fate determinants in cerebral cortical cultures and in an Alzheimer disease mouse model (PrP-APP(SW)). Up-regulation of Mash1 and down-regulation of Olig2 were found in cerebral cortical cultures treated with Abeta-(1-42). Mash1 was expressed in nestin-positive immature cells. The majority of Mash1-positive cells in untreated cortical culture co-expressed Olig2. Abeta increased the proportion of Olig2-negative/Mash1-positive cells. A decrease in Olig2+ cells was also observed in the cerebral cortex of adult PrP-APP(SW) 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 down-regulation of Olig2 by Abeta in Mash1-overexpressing cells switches the cell fate to death. Maintaining Olig2 expression in differentiating cells could have therapeutic potential.

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