Aβ40 promotes neuronal cell fate in neural progenitor cells

Abstract

Sequential cleavage of the amyloid precursor protein (APP) by β- and then γ- secretase gives rise to Aβ1-40 (Aβ40), a major species of Aβ (β-amyloid) produced by neurons under physiological conditions. Aβ1-42 (Aβ42), a minor species of Aβ, is also produced by a similar but less understood mechanism of the γ-secretase. The physiological functions of these Aβ species remain to be defined. In this report, we demonstrate that freshly prepared soluble Aβ40 significantly promotes neurogenesis in primary neural progenitor cells (NPCs). First, Aβ40 increases neuronal markers as determined by NeuN expression and Tuj1 promoter activity, differing from Aβ42, which induces astrocyte markers in NPCs. Second, Aβ40 induces neuronal differentiation at the end of S-phase in the cell cycle. Third, Aβ40 promotes NPC entry into S-phase, playing a role in NPC self-renewal. Interestingly, Aβ40 does not significantly increase apoptotic indexes such as DNA condensation and DNA fragmentation. In addition, Aβ40 does not augment caspase-3 activation in NeuN+ or nestin+ cells. Collectively, this report provides strong evidence that Aβ40 is a neurogenic factor and suggests that the debilitated function of Aβ40 in neurogenesis may account for the shortage of neurons in Alzheimer's disease.