Aβ oligomers promote oligodendrocyte differentiation and maturation via integrin β1 and Fyn kinase signaling

Alzheimer's disease (AD) is characterized by a progressive cognitive decline that correlates with the levels of amyloid beta-peptide (A beta) oligomers. Strong evidences connect changes of oligodendrocyte function with the onset of neurodegeneration in AD. However, the mechanisms controlling oligodendrocyte responses to A beta are still elusive. Here, we tested the role of A beta in oligodendrocyte differentiation, maturation, and survival in isolated oligodendrocytes and in organotypic cerebellar slices. We found that A beta peptides specifically induced local translation of 18.5-kDa myelin basic protein (MBP) isoform in distal cell processes concomitant with an increase of process complexity of MBPexpressing oligodendrocytes. A beta oligomers required integrin beta 1 receptor, Src-family kinase Fyn and Ca2+/CaMKII as effectors to modulate MBP protein expression. The pharmacological inhibition of Fyn kinase also attenuated oligodendrocyte differentiation and survival induced by A beta oligomers. Similarly, using ex vivo organotypic cerebellar slices A beta promoted MBP upregulation through Fyn kinase, and modulated oligodendrocyte population dynamics by inducing cell proliferation and differentiation. Importantly, application of A beta to cerebellar organotypic slices enhanced remyelination and oligodendrocyte lineage recovery in lysolecithin (LPC)-induced demyelination. These data reveal an important role of A beta in oligodendrocyte lineage function and maturation, which may be relevant to AD pathogenesis.