Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer's disease mouse model
| Autor: | Kiara Freitag, Nele Sterczyk, Sarah Wendlinger, Benedikt Obermayer, Julia Schulz, Vadim Farztdinov, Michael Mülleder, Markus Ralser, Judith Houtman, Lara Fleck, Caroline Braeuning, Roberto Sansevrino, Christian Hoffmann, Dragomir Milovanovic, Stephan J. Sigrist, Thomas Conrad, Dieter Beule, Frank L. Heppner, Marina Jendrach |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Spermidine
Immunology metabolism [Amyloid beta-Peptides] genetics [Alzheimer Disease] pharmacology [Spermidine] Cellular and Molecular Neuroscience Mice Dietary supplement Neuroinflammation Phagocytosis Ecology Evolution & Ethology Alzheimer Disease Autophagy drug therapy [Alzheimer Disease] Animals Single nuclei sequencing ddc:610 Computational & Systems Biology Chemical Biology & High Throughput Amyloid beta-Peptides General Neuroscience therapeutic use [Spermidine] drug effects [Amyloid beta-Peptides] Disease Models Animal Metabolism Neurology Astrocytes Neuroinflammatory Diseases Liquid chromatography tandem mass spectrometry Synthetic Biology Microglia Technology Platforms drug therapy [Neuroinflammatory Diseases] Alzheimer’s disease metabolism [Alzheimer Disease] |
| Zdroj: | Journal of neuroinflammation 19, 172 (2022). doi:10.1186/s12974-022-02534-7 |
| DOI: | 10.1186/s12974-022-02534-7 |
| Popis: | Background Deposition of amyloid beta (Aβ) 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 Aβ pathology and glial cell-mediated neuroinflammation. Results Oral treatment of the amyloid prone AD-like APPPS1 mice with spermidine reduced neurotoxic soluble Aβ 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 Aβ 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 Aβ degradation and to counteract glia-mediated neuroinflammation in AD pathology. |
| Databáze: | OpenAIRE |
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