The autophagy activator Spermidine ameliorates Alzheimer’s disease pathology and neuroinflammation in mice

Abstract

Deposition of amyloid beta (Aβ) and phosphorylated Tau along with microglia- and astrocyte-mediated neuroinflammation are prominent pathogeneic features of Alzheimer’s Disease (AD). In recent years, impairment of autophagy has also been shown to contribute to AD progression. Here, we provide evidence that oral treatment of amyloid-prone AD-like APPPS1 mice with the autophagy activator Spermidine, a small body-endogenous polyamine often used as dietary supplement, decreased neuroinflammation and reduced neurotoxic soluble Aβ at both early and late stages of AD. Mechanistically, Spermidine induced autophagy in microglia as well as in astrocytes, which subsequently impacted TLR3- and TLR4-mediated inflammatory processes by decreasing cytotoxicity, inflammasome activity and NF-κB signalling. Our data highlight that autophagy targets the inflammatory response of glial cells and emphasize the potential of orally administered autophagy-activating drugs such as Spermidine to interfere with AD progression.

Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia

“…Although the exact mechanisms were not elucidated, the authors speculated that autophagy [350,351] may play a role in the preservation of memory capacity in ageing. This is further reinforced by recent studies on mice which showed that supplementation by spermidine and spermine may delay brain ageing and alleviate AD pathology via mechanisms involving autophagy, promotion of ATP, reduction of ROS [353,354] and inflammation [355]. Maglione and colleagues showed that spermidine offered protection from synaptic alterations in the hippocampus of ageing mice extending their lifespan with a late treatment (starting at 18 months) [356].…”

Effects of lifespan-extending interventions on cognitive healthspan

“…In a preprint from Charité – Universitätsmedizin Berlin, dietary spermidine supplementation induced autophagy in microglia and astrocytes of APP/PS1 mouse model by decreasing the inflammasome and nuclear factor (NF)- κ B pathway activities (Ref. 234). In contrast, a tau-induced mouse model (rTg4510) exhibited an accumulation of acetylated spermidine levels, and knock-out of spermidine/spermine-N1-acetyltransferase had beneficial effects on rota-rod task, marble burying task and elevated plus-maze (Ref.…”

Resolving Geroplasticity to the Balance of Rejuvenins and Geriatrins

“…Polyamines have anti-inflammatory and anti-apoptotic effects, e.g., spermidine supplementation was shown to reduce accumulation of neurotoxic soluble Aβ in early as well as late stages of Alzheimer’s disease [ 396 , 424 , 425 ]. In thioacetamide (TAA)-induced acute liver injury, spermine exerted its anti-inflammatory action by inhibiting M1 polarization, while promoting M2 polarization of Kupffer cells (KCs), decreasing their STAT1 activation, reducing the levels of IL1-β, and iNOS, and increasing STAT6 activation.…”