Phospholipase D Family Member 4 Regulates Microglial Phagocytosis and Remyelination via the AKT Pathway in a Cuprizone-Induced Multiple Sclerosis Mouse Model.

Autor: Sun R; Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China., Ma T; Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China., Zhao Z; Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China., Gao Y; Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China., Feng J; Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China., Yang X; Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China.
Jazyk: angličtina
Zdroj: CNS neuroscience & therapeutics [CNS Neurosci Ther] 2024 Nov; Vol. 30 (11), pp. e70111.
DOI: 10.1111/cns.70111
Abstrakt: Aims: Remyelination is an endogenous repair process that is often deficient in multiple sclerosis (MS). Stimulation of remyelination is thought to help limit the progression of MS. This study aimed to investigate the expression pattern and function of a microglial phagocytosis-related gene, phospholipase D family member 4 (PLD4), in a cuprizone (CPZ)-induced MS mouse model.
Methods: The extent of remyelination was assessed using LFB staining. Myelin phagocytosis assay was used to investigate the effect of Pld4 on microglial phagocytic activity.
Results: Pld4 was upregulated in the corpus callosum during demyelination and remyelination. AAV9-mediated Pld4 deficiency impaired remyelination and reduced the number of Olig2-positive cells. In the corpus callosum of Pld4-deficient mice, the microglial phagocytosis marker MAC2 was reduced, accompanied by inhibition of TrkA/AKT signaling. Similarly, the phagocytosis assay showed that Pld4 knockdown significantly inhibited myelin debris phagocytosis by BV2 cells. The AKT activator SC79 reversed the Pld4 deficiency-induced inhibition of microglial phagocytic activity and rescued the impaired remyelination in Pld4-deficient mice.
Conclusion: PLD4 is upregulated in CPZ-induced MS and modulates microglial phagocytosis and remyelination via the AKT pathway. Our findings provide experimental evidence for a better understanding of the molecular mechanism of MS.
(© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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