Amyloid β Peptides Promote Autophagy-Dependent Differentiation of Mouse Neural Stem Cells

Although regarded as neurotoxic, amyloid beta (A beta) peptides may also mediate a wide range of nonpathogenic processes. Autophagy has been implicated in A beta-mediated effects, although its precise function in neural differentiation remains unknown. Here, we addressed the role of different A beta fragments in neural stem cell (NSC) proliferation and differentiation, and investigated whether autophagy is involved in A beta-induced alterations of neural fate. Our results demonstrate that neuronal and glial-specific protein markers are significantly induced by both A beta(1-40) and A beta(1-42). However, A beta(1-40) preferentially enhances neurogenesis of NSCs, as determined by beta III-tubulin, NeuN, and MAP2 neuronal marker immunoreactivity, while A beta(1-42) appears to favor gliogenesis. In contrast, A beta(25-35) does not influence NSC fate. The effect of A beta(1-40) on neurogenesis is partially dependent on its role in NSC self-renewal as both S-phase of the cell cycle and BrdU labeling were markedly increased. Nevertheless, A beta(1-40) resulted also in increased Tuj1 promoter activity. Autophagy, assessed by conversion of endogenous LC3-I/II, fluorescence of pGFP-LC3-transfected cells, and Atg9 protein levels, was evident in both A beta(1-40)- and A beta(1-42)-treated NSCs, independently of reactive oxygen species production and apoptosis. Finally, inhibition of autophagy by pharmacologic means abrogated A beta-induced lineage-specific protein markers. These results support distinct roles for different A beta peptides in NSC fate decision and underline the importance of autophagy control of this process.