A novel culprit in glucose hypometabolism in Alzheimer’s disease
Bibliographic record
Abstract
Abstract Background Alzheimer’s disease is characterized by early decreases in cerebral glucose metabolism which are linked to reduced glucose transporter 1 (GLUT1) expression at the blood‐brain barrier (BBB). Another key disease hallmark is the abundance of Aβ peptides as plaques in the brain which arise from the processing of the amyloid precursor protein (APP). Autosomal dominant inherited mutations causatively link APP itself to AD, rendering it imperative to fully understand APP’s physiological functions to define the underlying biology of AD. Previous studies in APP knockout (KO) mice implicate APP in metabolic processes such as mitochondrial function and insulin action. However, GLUT1 regulation as well as glucose metabolism at the BBB has yet to be investigated. Method We use APP KO mouse embryonic fibroblasts (MEFs), mouse primary cerebral endothelial cells, and vessels enriched from mouse brains to study GLUT1 physiology. RNAseq data was collected in MEFs to determine transcriptional changes underlying studied phenotypes. Result Seahorse analysis of APP KO MEFs revealed a 50% decrease in glycolytic activity and 75% decrease in mitochondrial respiration as compared to control. Glucose uptake was also significantly decreased in the absence of APP. These metabolic defects were underlined by a 2‐fold decrease in GLUT1 total expression and a 5‐fold decrease in GLUT1 cell surface levels. The investigation of signaling pathways responsible for GLUT1 upregulation showed that PI3K/Akt/mTORC pathway was downregulated in APP KO MEFs as compared to control. Primary cerebral endothelial cells and vessels recapitulated the decrease in GLUT1 expression as well as decreased activation of the PI3K/Akt/mTORC pathway, suggesting a completely novel role for APP in cerebral glucose metabolism. Analysis of RNAseq data collected in MEFs for pathways regulating glucose metabolism revealed widespread changes in extracellular matrix gene expression. Conclusion Our findings posit APP as a major regulator of GLUT1 expression and glucose metabolism. This new perspective on APP is crucial for AD therapy as novel approaches could be developed to target decreased cerebral glucose metabolism.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".