Amyloid beta oligomers dysregulate oligodendrocyte differentiation and myelination via PKC in the zebrafish spinal cord

Abstract

Amyloid {beta} oligomers (A{beta}o) have been proposed as candidates to induce oligodendrocyte (OL) and myelin dysfunctions in early stages of Alzheimers disease (AD) pathology. Nevertheless, little is known about how A{beta}o affect OL differentiation and myelination in vivo, and the underlying molecular mechanisms. In this study, we explored the effects of a brain intraventricular injection of A{beta}o on OLs and myelin in the developing spinal cord of zebrafish larvae. Using quantitative fluorescent in situ RNA hybridization assays, we demonstrated that A{beta}o altered myrf and mbp mRNA levels and the regional distribution of mbp during larval development, suggesting an early differentiation of OLs. Through live imaging of Tg(myrf:mScarlet) and Tg(mbp:tagRFP) zebrafish lines, both crossed with Tg(olig2:EGFP), we found that A{beta}o increased the number of myrf+ and mbp+ OLs in the dorsal spinal cord at 72 hpf and 5 dpf, respectively, without affecting total cell numbers. Furthermore, A{beta}o also increased the number of myelin sheaths per OL and the number of myelinated axons in the dorsal spinal cord compared to vehicle-injected control animals. Interestingly, the treatment of A{beta}o-injected zebrafish with the pan-PKC inhibitor Go6983 restored the aforementioned alterations in OLs and myelin to control levels. Altogether, not only do we demonstrate that A{beta}o induce a precocious oligodendroglial differentiation leading to dysregulated myelination, but we also identified PKC as a key player in A{beta}o-induced pathology.