2. Academic Validation
  3. Inhibition of repulsive guidance molecule A ameliorates diabetes-induced cognitive decline and hippocampal neurogenesis impairment in mice

Inhibition of repulsive guidance molecule A ameliorates diabetes-induced cognitive decline and hippocampal neurogenesis impairment in mice

  • Commun Biol. 2025 Feb 19;8(1):263. doi: 10.1038/s42003-025-07696-7.
Hiroki Uno 1,  Takahide Itokazu 2 3,  Toshihide Yamashita 4 5 6 7
Affiliations

Affiliations

  • 1 Department of Molecular Neurosciences, Graduate School of Medicine, Osaka University, Suita, Japan.
  • 2 Department of Molecular Neurosciences, Graduate School of Medicine, Osaka University, Suita, Japan. t.itokazu@molneu.med.osaka-u.ac.jp.
  • 3 Department of Neuro-Medical Science, Graduate School of Medicine, Osaka University, Suita, Japan. t.itokazu@molneu.med.osaka-u.ac.jp.
  • 4 Department of Molecular Neurosciences, Graduate School of Medicine, Osaka University, Suita, Japan. yamashita@molneu.med.osaka-u.ac.jp.
  • 5 Department of Neuro-Medical Science, Graduate School of Medicine, Osaka University, Suita, Japan. yamashita@molneu.med.osaka-u.ac.jp.
  • 6 WPI-Immunology Frontier Research Center, Osaka University, Suita, Japan. yamashita@molneu.med.osaka-u.ac.jp.
  • 7 Graduate School of Frontier Biosciences, Osaka University, Suita, Japan. yamashita@molneu.med.osaka-u.ac.jp.
PMID: 39972167 DOI: 10.1038/s42003-025-07696-7
Abstract

Although diabetes mellitus is strongly associated with dementia, the mechanism underlying diabetes-induced cognitive dysfunction has not been clarified. Here, we demonstrate the vital role of repulsive guidance molecule A (RGMa) in the regulation of adult hippocampal neurogenesis and cognitive impairment under diabetic conditions. In type 2 diabetic db/db mice and streptozotocin-mediated type 1 diabetic mice, RGMa is upregulated in the granular cell layer of the dentate gyrus. Additionally, both neural stem cells (NSCs) and immature neurons express its receptor, neogenin. In vitro experiments revealed that high glucose-conditioned hippocampal neurons inhibited the differentiation of NSCs, and the application of an anti-RGMa antibody restored it. The treatment with an anti-RGMa antibody ameliorated diabetes-induced cognitive decline and impairment of hippocampal neurogenesis. These findings suggest that the RGMa negatively regulates hippocampal neurogenesis and is involved in diabetes mellitus-induced cognitive decline.

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