GM1 modulates amyloid‐beta activation of NLRP3 inflammasome in microglia through Akt/mTOR‐mediated regulation of autophagy

Abstract

AbstractBackgroundMicroglia are cellular players underlying neuroinflammation, a major driver of Alzheimer’s Disease (AD) pathogenesis. In the AD brain, microglia are observed surrounding beta‐amyloid (Aβ) plaque and are responsible for amyloid clearance. However, chronic microglia activation by amyloid leads to microglia dysfunction, including autophagy dysregulation, degradative impairment, and a prominent pro‐inflammatory response that exacerbates plaque deposition and neurodegeneration (Hickman et al., 2008). The key to targeting neuroinflammation may be GM1 ganglioside. Gangliosides are glycosphingolipids highly enriched in the central nervous system and play a critical role in membrane organization and signal transduction. Notably, Ganglioside dysregulation has been observed in pre‐clinical and clinical models of AD (Svennerholm et al., 2008). GM1, the most abundant ganglioside in the adult brain, serves a neuroprotective and anti‐inflammatory role, but the mechanism remains unknown (Galleguillos et al., 2022). This study aims to interrogate the cell‐specific mechanism and therapeutic potential of GM1 to alleviate microglia inflammation in response to amyloid. We hypothesize that GM1 ganglioside is protective against neuroinflammation by upregulating microglia autophagy in AD.MethodBV‐2 microglia culture was activated by oligomeric Aβ (Aβo) exposure with or without GM1 pre‐treatment. Cells were treated with rapamycin, an mTORC1 inhibitor and autophagy modulation. NLRP3 inflammasome activation was assessed by pro‐inflammatory gene transcription and cleaved caspase‐1 and IL1β release. Autophagy was assessed by p62 and LC3 II/I protein expression. Microglia ganglioside abundance was measured using electrospray‐ionization mass spectrometry.ResultAβo significantly increased microglial NLRP3 inflammasome priming, suppressed autophagy flux, and increased GM1 degradation compared to control. GM1 pre‐treatment attenuated Aβo inflammasome activation and promoted autophagy initiation by downregulating Akt and mTOR phosphorylation. The protective effect of GM1 involves membrane signalling receptors such as Trem2.ConclusionGM1 ganglioside is protective against amyloid‐mediated microglia inflammation by suppressing NLRP3 inflammasome priming and restoring autophagy via Akt/mTOR signalling pathways. GM1 upregulation of autophagy demonstrates a promising therapeutic target to resolve neuroinflammation and halt the accelerated progression of AD.