Trpc6 knockout improves behavioral dysfunction and reduces Aβ production by inhibiting CN-NFAT1 signaling in T2DM mice.

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  • Additional Information
    • Source:
      Publisher: Academic Press Country of Publication: United States NLM ID: 0370712 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2430 (Electronic) Linking ISSN: 00144886 NLM ISO Abbreviation: Exp Neurol Subsets: MEDLINE
    • Publication Information:
      Publication: Orlando Fl : Academic Press
      Original Publication: New York.
    • Subject Terms:
      Diabetes Mellitus, Type 2*/metabolism ; Diabetes Mellitus, Experimental*/complications; Mice ; Animals ; TRPC6 Cation Channel/metabolism ; Amyloid beta-Peptides/metabolism ; Blood Glucose ; Calcium/metabolism ; Neuroinflammatory Diseases ; Signal Transduction ; Mice, Knockout
    • Abstract:
      As the prevalence of diabetes and health awareness increase, type 2 diabetes mellitus -associated cognitive dysfunction is receiving increasing attention. However, the pathogenesis is not entirely understood. Transient receptor potential cation channel 6 (TRPC6) is highly correlated with intracellular Ca 2+ concentrations, and neuronal calcium overload is an important cause of cognitive dysfunction. In the present study, we investigated the effect and mechanism of Trpc6 knockout in high-fat diet and streptozotocin-induced T2DM mice. The body weight and fasting blood glucose were recorded during the experiment. Behavioral dysfunction was detected using the open field test (OFT), elevated plus maze (EPM), hole-board test (HBT), Morris water maze (MWM) test and contextual fear conditioning (CFC) test. Nissl and H&E staining were used to examine neuronal damage. Western blot, quantitative real-time polymerase chain reaction (q-PCR), and immunofluorescence were performed to detect amyloid beta protein (Aβ) deposition and related indicators of neurological impairments in the cerebral cortex and hippocampus. The results indicated that Trpc6 knockout inhibited body weight loss and fasting blood glucose increase, improved spontaneous activity, learning and memory dysfunction, and alleviated neuroinflammation and neuronal damage in T2DM mice. The further results demonstrated that Trpc6 knockout decreased Aβ generation and deposition, and reduced the expressions of inflammasome-related proteins in T2DM mice. In addition, Trpc6 knockout inhibited intracellular calcium overload in diabetic mice and primary cultured hippocampal neurons, which in turn suppressed CN and NFAT1 expression. These data suggest that Trpc6 knockout may inhibit the CN-NFAT1 signaling pathway by decreasing intracellular calcium overload in the brain of T2DM mice, which consequently reduce Aβ deposition and neuroinflammation, and ultimately delay the development of T2DM-associated cognitive dysfunction.
      Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests.
      (Copyright © 2023. Published by Elsevier Inc.)
    • Comments:
      Erratum in: Exp Neurol. 2024 Mar 28;:114719. (PMID: 38553399)
    • Contributed Indexing:
      Keywords: Amyloid β-protein; Calcineurin; Calcium overload; Nuclear factor of activated T cells; T2DM-associated cognitive dysfunction; Transient receptor potential canonical channel 6
    • Accession Number:
      0 (TRPC6 Cation Channel)
      0 (Amyloid beta-Peptides)
      0 (Blood Glucose)
      SY7Q814VUP (Calcium)
      0 (Trpc6 protein, mouse)
    • Publication Date:
      Date Created: 20230215 Date Completed: 20230405 Latest Revision: 20240329
    • Publication Date:
      20240330
    • Accession Number:
      10.1016/j.expneurol.2023.114350
    • Accession Number:
      36791875