GM1 modulates amyloid‐beta activation of NLRP3 inflammasome in microglia through Akt/mTOR‐mediated regulation of autophagy
Bibliographic record
Abstract
Abstract Background Microglia 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. Method BV‐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. Result Aβo 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. Conclusion GM1 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".