P2‐037: THE QUEST FOR EARLY REVERSIBLE CHANGES IN ALZHEIMER'S DISEASE: MASS SPECTROMETRIC IMAGING OF GANGLIOSIDES IN A NOVEL TRANSGENIC RAT MODEL OF PRODROMAL AD
Bibliographic record
Abstract
Identifying the earliest cellular changes that lead to Alzheimer's disease (AD) is an important step towards preventing the disease. In search of such changes, we investigate membrane lipids called gangliosides that are essential for cell signaling and survival. The expression pattern of ganglioside species can change in response to stress, and in turn, altered membrane lipid composition can increase a cell's vulnerability to stressors. Gangliosides are implicated in a number of neurodegenerative diseases, including Alzheimer's disease (AD), yet whether gangliosides play an important role in the earliest stages of AD development remains unresolved. We hypothesize that changes in membrane lipid composition, including gangliosides, may be evident in the elderly brain during the prodromal stages of AD. Such membrane alterations may render the aging brain more vulnerable, and set in motion a downward spiral of pathologic events, culminating in the development of AD. llIdentifying the earliest cellular changes that lead to Alzheimer's disease (AD) is an important step towards preventing the disease. In search of such changes, we investigate membrane lipids called gangliosides that are essential for cell signaling and survival. The expression pattern of ganglioside species can change in response to stress, and in turn, altered membrane lipid composition can increase a cell's vulnerability to stressors. Gangliosides are implicated in a number of neurodegenerative diseases, including Alzheimer's disease (AD), yet whether gangliosides play an important role in the earliest stages of AD development remains unresolved. We hypothesize that changes in membrane lipid composition, including gangliosides, may be evident in the elderly brain during the prodromal stages of AD. Such membrane alterations may render the aging brain more vulnerable, and set in motion a downward spiral of pathologic events, culminating in the development of AD.the earliest cellular changes that lead to Alzheimer's disease (AD) is an important step towards preventing the disease. In search of such changes, we investigate membrane lipids called gangliosides that are essential for cell signaling and survival. The expression pattern of ganglioside species can change in response to stress, and in turn, altered membrane lipid composition can increase a cell's vulnerability to stressors. Gangliosides are implicated in a number of neurodegenerative diseases, including Alzheimer's disease (AD), yet whether gangliosides play an important role in the earliest stages of AD development remains unresolved. We hypothesize that changes in membrane lipid composition, including gangliosides, may be evident in the elderly brain during the prodromal stages of AD. Such membrane alterations may render the aging brain more vulnerable, and set in motion a downward spiral of pathologic events, culminating in the development of AD. To model the prodromal stage of AD in the elderly brain, we use a novel transgenic rat strain. APP21 transgenic (tg) rats express human APP Swe/Ind in high quantities but do not develop histological hallmarks of AD spontaneously as they age. Yet, these animals are susceptible to developing pathological hallmarks of AD when challenged, for example with AD brain extracts. In brain sections from APP21 tg animals, we imaged and profiled gangliosides based on their chemical structure using matrix-associated-laser-desorption/ionization imaging mass spectrometry (MALDI-IMS). This innovative technology allows us to visualize changes in ganglioside expression profiles within a neuroanatomical context, and to relate these profiles to neuropathological events. To test our hypothesis, we harvested brains from APP21 tg rats and age-matched wildtype rats at different ages. Brain sections were imaged with MALDI-IMS and screened histologically for any pathology related to AD (Abeta, plaques, astrogliosis, activated microglia). A comparison of brain ganglioside expression between APP21 tg rats and wildtype animals will be presented. If our hypothesis is confirmed, an intervention aimed at stabilizing membrane lipid composition in individuals at risk of developing AD may make the aging brain more resistant to neurodegenerative challenges.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.002 |
| 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".