Distinct disruptions in Land's cycle remodeling of glycerophosphocholines in murine cortex mark symptomatic onset and progression in two Alzheimer's disease mouse models
Bibliographic record
Abstract
Abstract Changes in glycerophosphocholine metabolism are observed in Alzheimer's disease; however, it is not known whether these metabolic disruptions are linked to cognitive decline. Here, using unbiased lipidomic approaches and direct biochemical assessments, we profiled Land's cycle lipid remodeling in the hippocampus, frontal cortex, and temporal‐parietal‐entorhinal cortices of human amyloid beta precursor protein (ΑβPP) over‐expressing mice. We identified a cortex‐specific hypo‐metabolic signature at symptomatic onset and a cortex‐specific hyper‐metabolic signature of Land's cycle glycerophosphocholine remodeling over the course of progressive behavioral decline. When N5 TgCRND8 and ΑβPPSwe/PSIdE9 mice first exhibited deficits in the Morris Water Maze, levels of lyso‐phosphatidylcholines, LPC(18:0/0:0), LPC(16:0/0:0), LPC(24:6/0:0), LPC(25:6/0:0), the lyso‐platelet‐activating factor (PAF), LPC(O‐18:0/0:0), and the PAF, PC(O‐22:6/2:0), declined as a result of reduced calcium‐dependent cytosolic phospholipase A2α (cPLA2α) activity in all cortices but not hippocampus. Chronic intermittent hypoxia, an environmental risk factor that triggers earlier learning memory impairment in ΑβPPSwe/PSIdE9 mice, elicited these same metabolic changes in younger animals. Thus, this lipidomic signature of phenoconversion appears age‐independent. By contrast, in symptomatic N5 TgCRND8 mice, cPLA2α activity progressively increased; overall Lyso‐phosphatidylcholines (LPC) and LPC(O) and PC(O‐18:1/2:0) levels progressively rose. Enhanced cPLA2α activity was only detected in transgenic mice; however, age‐dependent increases in the PAF acetylhydrolase 1b α1 to α2 expression ratio, evident in both transgenic and non‐transgenic mice, reduced PAF hydrolysis thereby contributing to PAF accumulation. Taken together, these data identify distinct age‐independent and age‐dependent disruptions in Land's cycle metabolism linked to symptomatic onset and progressive behavioral decline in animals with pre‐existing Αβ pathology. Open science badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/ . image
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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) | 0.001 | 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 | 0.001 |
| 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".