Journal Article

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

Sterczyk, Nele, Hoffmann, Christian, Farztdinov, Vadim, Wendlinger, Sarah, Jendrach, Marina, Fleck, Lara, Braeuning, Caroline, Sansevrino, Roberto, Milovanovic, Dragomir, Houtman, Judith, Obermayer, Benedikt, Schulz, Julia, Mülleder, Michael, Sigrist, Stephan J., Freitag, Kiara, Beule, Dieter, Conrad, Thomas, Heppner, Frank L., Ralser, Markus

2022

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Alzheimer's disease / Astrocytes / Autophagy / Axl protein / Biomedical and Life Sciences / Biomedicine / Brain / Care and treatment / Cell migration / Cytokines / Cytoskeleton / Development and progression / Dietary supplements / Dosage and administration / Glial cells / Immunology / Inflammasomes / Inflammation / Microglia / Neurobiology / Neurodegenerative diseases / Neuroinflammation / Neurology / Neuronal-glial interactions / Neurosciences / Neurotoxicity / Pathology / Phagocytosis / Polyamines / Proteins / Proteomes / Spermidine / Tau protein / Testing / TLR3 protein / TLR4 protein / Toll-like receptors