Quintela, T. . 1, 2, 3 , Matute, C. . 1, 2, 3 & Alberdi, E. 1, 2, 3
1 Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), Leioa, Spain
2 Achucarro Basque Center for Neuroscience, UPV/EHU, Zamudio, Spain
3 Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED)
Amyloid beta (Abeta) oligomers are key peptides involved in Alzheimer´s disease (AD) pathogenesis. The effects of these oligomers on white matter, and specifically on oligodendrocytes (OLG) are still poorly understood, even though their damage may contribute to cognitive decline in AD. Here, we have investigated the role of Abeta oligomers in OLG differentiation and myelination in vitro and in vivo. Using a panel of developmental stage-specific antigenic markers, we observed that Abeta oligomers modified the differentiation pattern, regulating the transition of early progenitors to the late progenitor stage (O4 positive cells) and to the inmature to mature OLG stage (MBP positive cells) in OLG in vitro. To further investigate the pathway underlying Abeta-mediated OLG differentiation, we analyzed the phosphorylation levels of three key proteins involved in myelin synthesis, AKT, ERK and CREB. We found that Abeta oligomers promoted a sustained AKT dephosphorylation, and ERK and CREB phosphorylation and the specific pharmacological inhibition of these pathways reduced the Abeta-induced MBP upregulation in cultured OLGs. Furthermore, Abeta oligomers increased the MBP levels in cultured cerebellar slices in control and in lysolecithin-induced demyelination conditions. This Abeta-mediated myelin upregulation was confirmed in the corpus callosum of a mouse model of AD. Our data suggest that Abeta oligomers induce OLG differentiation through MAPK/ERK, PI3K/AKT and PKA/CREB signaling pathways, which may be relevant to understand AD pathophysiology.