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bioRxiv · 10.1101/2020.03.30.015297

Essential roles of plexin-B3+ oligodendrocyte precursor cells in the pathogenesis of Alzheimer's disease

Nihonmatsu-Kikuchi, N.·Yu, X.-J.·Matsuda, Y.·Ozawa, N.·Ito, T.·Satou, K.·Kaname, T.·Takashima, A.·Toru, S.·Hirokawa, K.·Hasegawa, M.·Uchihara, T.·Tatebayashi, Y.
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Abstract

The roles played by oligodendrocyte (OL) lineage cells, the largest glial population in the adult CNS, in the pathogenesis of Alzheimers disease (AD) remain elusive. Here, we show a newly developed culture method for adult OL progenitor cells (aOPCs) and identify novel plexin-B3-expressing (plexin-B3+) aOPCs as potential amyloid {beta} peptides (A{beta})-secreting cells. Fibroblast growth factor 2 (FGF2) promotes the survival and proliferation of aOPCs in a serum-free defined medium. Although the whole expression profiles of the expanded aOPCs closely resemble those of in vivo OPCs, we found a subpopulation (up to 5%) of plexin-B3+/olig2+ aOPCs in the cultures growing in FGF2. FGF2 withdrawal decreased NG2+, but increased plexin-B3+ aOPCs with increased APP expression, A{beta}1-40, -42 secretions and A{beta}1-42/total A{beta} ratios in association with cored senile plaque-like morphological changes. In vivo, plexin-B3+ aOPCs are distributed throughout the adult brain, although less densely so than NG2+ aOPCs. Spreading depolarization, a type of brain injury, induced unique delayed cortical plexin-B3+ aOPC gliosis in the ipsilateral, but not in the contralateral, remote cortex. In AD brains, virtually all senile plaques in the cortex were immunostained with plexin-B3 antibodies and the levels of cortical plexin-B3 expression increased significantly in the Salcosyl-soluble fractions. These findings suggest that plexin-B3+ aOPCs play important roles in the pathogenesis of AD most likely as a natural A{beta} source.

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Nihonmatsu-Kikuchi, N., Yu, X.-J., Matsuda, Y., Ozawa, N., Ito, T., Satou, K., Kaname, T., Takashima, A., Toru, S., Hirokawa, K., Hasegawa, M., Uchihara, T., Tatebayashi, Y.. 2020-03-31. Essential roles of plexin-B3+ oligodendrocyte precursor cells in the pathogenesis of Alzheimer's disease. https://doi.org/10.1101/2020.03.30.015297

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