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

Abstract

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.

Spermidine Rescues Bioenergetic and Mitophagy Deficits Induced by Disease-Associated Tau Protein

“…Dietary supplementation with spermidine (3 mM in drinking water for up to 290 days) was recently shown to decrease toxic soluble amyloid-β (Aβ) levels, as well as neuroinflammation in a mouse model of AD-related amyloidopathy (APPPS1 mice) [ 28 ]. Spermidine mostly acted on microglial cells and upregulated the autophagy pathway, leading to an increase in Aβ clearance.…”

An in silico investigation on the interactions of curcumin and epigallocatechin-3-gallate with NLRP3 Inflammasome complex

“…MCC950 blocks the release of IL-1β, which inhibits NLRP3 inflammasome. Furthermore, it specifically targets the NLRP3 NATCH domain and interferes with the Walker B motif function, thus preventing the conformational change and oligomerization of NLRP3 [46][47][48]. In contrast, molecular interaction studies suggest that the binding energies of curcumin and MCC950 are almost comparable, whereas EGCG has greater binding energies than curcumin and MCC950.…”

Role of microglia autophagy and mitophagy in age-related neurodegenerative diseases

“…In vitro , spermidine increased the expression of the autophagy-associated gene ETS2, as well as microglia cluster 2, both of which enhance phagocytosis and degradation of Aβ. Furthermore, spermidine may have a direct inhibition on Aβ-induced neuroinflammation by reducing NF-κB phosphorylation levels and down-regulating inflammatory cytokine-related genes ( Freitag et al, 2022 ).…”