Aβ40 promotes neuronal cell fate in neural progenitor cells

Sequential cleavage of the amyloid precursor protein (APP) by beta- and then gamma- secretase gives rise to A beta(1-40) (A beta 40), a major species of A beta (beta-amyloid) produced by neurons under physiological conditions. A beta(1-42) (A beta 42), a minor species of A beta, is also produced by a similar but less understood mechanism of the gamma-secretase. The physiological functions of these A beta species remain to be defined. In this report, we demonstrate that freshly prepared soluble A beta 40 significantly promotes neurogenesis in primary neural progenitor cells (NPCs). First, A beta 40 increases neuronal markers as determined by NeuN expression and Tuj1 promoter activity, differing from A beta 42, which induces astrocyte markers in NPCs. Second, A beta 40 induces neuronal differentiation at the end of S-phase in the cell cycle. Third, A beta 40 promotes NPC entry into S-phase, playing a role in NPC self-renewal. Interestingly, A beta 40 does not significantly increase apoptotic indexes such as DNA condensation and DNA fragmentation. In addition, A beta 40 does not augment caspase-3 activation in NeuN(+) or nestin(+) cells. Collectively, this report provides strong evidence that A beta 40 is a neurogenic factor and suggests that the debilitated function of A beta 40 in neurogenesis may account for the shortage of neurons in Alzheimer's disease.