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Amyloid‐β Dysregulates Oligodendroglial Lineage Cell Dynamics and Myelination via PKC in the Zebrafish Spinal Cord
Author(s) -
Balantzategi Uxue,
GamindeBlasco Adhara,
Kearns Christina A.,
BayónCordero Laura,
SánchezGómez María Victoria,
Zugaza José Luis,
Appel Bruce,
Alberdi Elena
Publication year - 2025
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.70015
Subject(s) - zebrafish , myelin , spinal cord , biology , olig2 , myelin basic protein , sox10 , neuroscience , oligodendrocyte , in situ hybridization , microbiology and biotechnology , central nervous system , messenger rna , embryo , biochemistry , gene , neural crest
ABSTRACT Soluble forms of amyloid‐β (Aβ) peptide have been proposed as candidates to induce oligodendrocyte (OL) and myelin dysfunctions in the early stages of Alzheimer's disease (AD) pathology. Nevertheless, little is known about how Aβ affects OL differentiation and myelination in vivo, and the underlying molecular mechanisms. In this study, we explored the effects of a brain intraventricular injection of Aβ on OLs and myelin in the developing spinal cord of zebrafish larvae. Using quantitative fluorescent in situ RNA hybridization assays, we demonstrated that Aβ 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 ( mbpa:tagRFP ) zebrafish lines, both crossed with Tg ( olig2:EGFP ), we found that Aβ 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, Aβ also increased the number of Sox10 + cells, myelin sheaths per OL, and the number of myelinated axons in the dorsal spinal cord at 8 dpf compared to vehicle‐injected control animals. Interestingly, the treatment of Aβ‐injected zebrafish with the pan‐PKC inhibitor Gö6983 restored the aforementioned alterations in OLs and myelin to control levels. Altogether, not only do we demonstrate that Aβ induces a precocious oligodendroglial differentiation leading to dysregulated myelination, but we also identified PKC as a key player in Aβ‐induced pathology.