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Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer’s disease mouse model

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Item Type:Article
Title:Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer’s disease mouse model
Creators Name:Freitag, K. and Sterczyk, N. and Wendlinger, S. and Obermayer, B. and Schulz, J. and Farztdinov, V. and Mülleder, M. and Ralser, M. and Houtman, J. and Fleck, L. and Braeuning, C. and Sansevrino, R. and Hoffmann, C. and Milovanovic, D. and Sigrist, S.J. and Conrad, T. and Beule, D. and Heppner, F.L. and Jendrach, M.
Abstract:BACKGROUND: Deposition of amyloid beta (Aß) and hyperphosphorylated tau along with glial cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimer's disease (AD). In recent years, impairment of autophagy has been identified as another important feature contributing to AD progression. Therefore, the potential of the autophagy activator spermidine, a small body-endogenous polyamine often used as dietary supplement, was assessed on Aß pathology and glial cell-mediated neuroinflammation. RESULTS: Oral treatment of the amyloid prone AD-like APPPS1 mice with spermidine reduced neurotoxic soluble Aß and decreased AD-associated neuroinflammation. Mechanistically, single nuclei sequencing revealed AD-associated microglia to be the main target of spermidine. This microglia population was characterized by increased AXL levels and expression of genes implicated in cell migration and phagocytosis. A subsequent proteome analysis of isolated microglia confirmed the anti-inflammatory and cytoskeletal effects of spermidine in APPPS1 mice. In primary microglia and astrocytes, spermidine-induced autophagy subsequently affected TLR3- and TLR4-mediated inflammatory processes, phagocytosis of Aß and motility. Interestingly, spermidine regulated the neuroinflammatory response of microglia beyond transcriptional control by interfering with the assembly of the inflammasome. CONCLUSIONS: Our data highlight that the autophagy activator spermidine holds the potential to enhance Aß degradation and to counteract glia-mediated neuroinflammation in AD pathology.
Keywords:Alzheimer’s Disease, Neuroinflammation, Microglia, Astrocytes, Autophagy, Spermidine, Dietary Supplement, Single Nuclei Sequencing, Liquid Chromatography Tandem Mass Spectrometry, Phagocytosis, Animals, Mice
Source:Journal of Neuroinflammation
Publisher:BioMed Central
Page Range:172
Date:2 July 2022
Official Publication:https://doi.org/10.1186/s12974-022-02534-7
PubMed:View item in PubMed

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