Bayon-Cordero, L. | Search bioRxiv

bioRxiv2024

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

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.

neuroscience↗

bioRxiv2022

GABABR agonist baclofen promotes central nervous system remyelination

Promoting remyelination - the endogenous response by which lost myelin sheaths are regenerated - is considered as a potential neuroprotective strategy to prevent/limit the development of permanent neurological disability in patients with multiple sclerosis (MS). To this end, a number of clinical trials are investigating the potential of existing drugs to enhance oligodendrocyte progenitor cell (OPC) differentiation, the process that fails in chronic MS lesions. As we previously reported that oligodendroglia lineage cells express GABAB receptors (GABABRs) both in vitro and in vivo, and that GABABR-mediated signaling enhances OPC differentiation and myelination in vitro, here we focused on the remyelinating potential of the best-known GABABR agonist baclofen (Bac), already approved to treat spasticity in MS. We demonstrated that Bac increases myelin protein production following lysolecithin (LPC)-induced demyelination in cerebellar ex vivo slices. In addition, Bac administration enhanced OPC differentiation and remyelination in LPC-induced spinal cord lesions in adult mice. Thus, our results suggest that Bac should be considered as a potential therapeutic agent, not only to treat spasticity, but also to improve remyelination in patients with MS.

neuroscience↗