Disordered ganglioside localization in the Alzheimer’s disease brain
Bibliographic record
Abstract
Abstract Background Alzheimer’s disease (AD) is a progressive dementia that impairs memory and cognition. Gangliosides are glycosphingolipids enriched within the central nervous system and known to alter the secondary structure of amyloid beta deposits, a hallmark of AD (Choo‐Smith et al., 1997). The ganglioside GM1 is known to exert neuroprotective properties and was proposed as a therapeutic for AD (Svennerholm, 1994). In support of this, intraventricular administration of GM1 decreased amyloid beta deposits and provided clinical benefit (Augustinsson et al., 1997). Pre‐clinical work has since demonstrated a shift from complex GM1 species to simple GM2 and GM3 is linked to neurodegenerative pathogenesis (Wang & Whitehead, 2020). However, the ganglioside GM1 also converts amyloid beta to a toxic form with beta sheet structure (Yamamoto et al., 2007), and acts as a seed for amyloid beta fibrillogenesis (Yanagisawa et al., 1995). It is possible that different GM1 subtypes may be responsible for varying affects. Understanding the profile of GM1 subtypes in the AD brain may be a key step in capitalizing on its therapeutic potential. We investigate the ratio between 18 and 20 carbon subtypes of GM1 and simple ganglioside species in post‐mortem human AD brain tissue and non‐AD controls. Brain regions interrogated include the entorhinal cortex, basal forebrain, anterior commissure and hippocampus. Method Neuroanatomical regions of interest (ROIs) were blocked from neuropathologically confirmed AD and non‐AD brains and stored in 10% formalin. Samples were prepared for matrix assisted laser desorption ionization imagining mass spectrometry (MALDI‐IMS) (Caughlin et al., 2017). MALDI‐IMS was performed in reflectron negative mode. Matching ROIs in AD and non‐AD samples (n = 5) were selected using TissueView software. Mass spectra were normalized by area under curve and peaks corresponding to gangliosides were statistically analyzed. Result Non‐AD brains demonstrated distinct d20:1/d18:1 ratios of both simple and complex gangliosides between different brain regions. This expression profile was lost in the AD brain samples. Additionally, a significant decrease in this ratio was observed in AD compared to non‐AD samples in several brain regions. Conclusion Ganglioside dysregulation and a decrease in the d20:1/d18:1 ratios in multiple brain regions are critical pathological biomarkers 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 | 0.001 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".