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

ABSTRACT: The role of oligodendrocyte lineage cells, the largest glial population in the adult central nervous system (CNS), in the pathogenesis of Alzheimer's disease (AD) remains elusive. Here, we developed a culture method for adult oligodendrocyte progenitor cells (aOPCs). Fibroblast growth factor 2 (FGF2) promotes survival and proliferation of NG2⁺ aOPCs in a serum-free defined medium; a subpopulation (~5%) of plexin-B3⁺ aOPCs was also found. FGF2 withdrawal decreased NG2⁺, but increased plexin-B3⁺ aOPCs and Aβ1-42 secretion. Plexin-B3⁺ aOPCs were distributed throughout the adult rat brain, although less densely than NG2⁺ aOPCs. Spreading depolarization induced delayed cortical plexin-B3⁺ aOPC gliosis in the ipsilateral remote cortex. Furthermore, extracellular Aβ1-42 accumulation was occasionally found around plexin-B3⁺ aOPCs near the lesions. In AD brains, virtually all cortical SPs were immunostained for plexin-B3, and plexin-B3 levels increased significantly in the Sarkosyl-soluble fractions. These findings suggest that plexin-B3⁺ aOPCs may play essential roles in AD pathogenesis, as natural Aβ-secreting cells.

SUBMITTER: Nihonmatsu-Kikuchi N

PROVIDER: S-EPMC8282672 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Nihonmatsu-Kikuchi Naomi N Yu Xiu-Jun XJ Matsuda Yoshiki Y Ozawa Nobuyuki N Ito Taeko T Satou Kazuhito K Kaname Tadashi T Iwasaki Yasushi Y Akagi Akio A Yoshida Mari M Toru Shuta S Hirokawa Katsuiku K Takashima Akihiko A Hasegawa Masato M Uchihara Toshiki T Tatebayashi Yoshitaka Y

Communications biology 20210715 1

The role of oligodendrocyte lineage cells, the largest glial population in the adult central nervous system (CNS), in the pathogenesis of Alzheimer's disease (AD) remains elusive. Here, we developed a culture method for adult oligodendrocyte progenitor cells (aOPCs). Fibroblast growth factor 2 (FGF2) promotes survival and proliferation of NG2+ aOPCs in a serum-free defined medium; a subpopulation (~5%) of plexin-B3+ aOPCs was also found. FGF2 withdrawal decreased NG2+< ...[more]

PMID: 34267322

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Project description:The Plexins family of proteins are well-characterized transmembrane receptors of semaphorins, axon guidance cue molecules, that mediate the cell attraction or repelling effects for such cues. Plexins and their ligands are involved in numerous cellular activities, such as motility, invasion, and adhesion to the basement membrane. The detachment of cells and the gain in motility and invasion are hallmarks of the cancer metastasis cascade, thus generating interest in exploring the role of plexins in cancer metastasis. Semaphorin-plexin complexes can act as tumor promoters or suppressors, depending upon the cancer type, and are under investigation for therapeutic purposes. Our group has identified Semaphorin-5A (SEMA5A)/Plexin-B3 as an attractive targetable complex for pancreatic cancer (PC) metastasis. However, our understanding of the Plexin-B3 function and pathological expression in PC is limited, and our present study delineates the role of Plexin-B3 in PC malignancy. We examined the pathological expression of Plexin-B3 in PC tumors and metastasis using a human tissue microarray, disease progression model of PDX-Cre-Kras(G12D) (KC) mice, and different metastatic sites obtained from the KrasG12D; Trp53R172H; Pdx1-Cre (KPC) mice model. We observed a higher Plexin-B3 expression in PC tumor cores than the normal pancreas, and different metastatic sites were positive for Plexin-B3 expression. However, in the KC mice model, the Plexin-B3 expression increased initially and then decreased with the disease progression. Next, to evaluate the functional role of Plexin-B3, we utilized T3M-4- and CD18/HPAF-Control and -Plexin B3 knockdown cells for different in vivo and in vitro studies. The knockdown of Plexin-B3 enhanced the in vitro cellular migration, invasiveness, and impaired colony formation in three-dimensional culture, along with an increase in cellular spread and remodeling of the actin filaments. We also observed a higher metastasis in nude mice injected with T3M-4- and CD18/HPAF-shPlexin-B3 cells compared to their respective control cells. Furthermore, we observed a lower number of proliferating Ki-67-positive cells and higher ALDH1-A1-positive cells in the tumors formed by Plexin-B3 knockdown cells compared to tumors formed by the control cells. Together, our data suggest that the loss of Plexin-B3 is associated with the interference of cell division machinery and the induction of stem cell-like characteristics in PC cells.

Dataset Information

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

Publications

Essential roles of plexin-B3<sup>+</sup> oligodendrocyte precursor cells in the pathogenesis of Alzheimer's disease.

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