Hypothalamic and metabolic alterations at a pre‐symptomatic stage of Alzheimer's Disease
Bibliographic record
Abstract
BACKGROUND: The hypothalamus is the brain's center for metabolic regulation. It controls energy homeostasis, adiposity and glucose metabolism, acting as a link between the brain and peripheral tissues. Alzheimer's Disease (AD) is a multifactorial neurodegenerative disease. Besides the well-known cognitive impairment, patients often exhibit metabolic disturbances, including insulin resistance, dyslipidemia and body-weight disorders. Interestingly, these comorbidities have been associated with hypothalamic dysfunction; however, the role of the hypothalamus in AD remains largely unexplored. In this study, we aimed to characterize early hypothalamic cellular changes and identify potentially associated metabolic alterations during the pre-symptomatic stage of AD using the 3xTg-AD mouse model. METHOD: To characterize hypothalamic cellular changes at a presymptomatic stage we performed single-cell RNA sequencing (scRNAseq) on microdissected hypothalami from 3-months old WT and 3xTg-AD mice. Bioinformatic analysis were conducted in R. To gain further insight into metabolic-related hypothalamic functions we performed body-weight and blood glucose measurements, analyzed body mass composition and weighted peripheral metabolic organs of 3-months old 3xTg-AD mice. Additionally, we conducted a pilot snRNAseq experiment using post-mortem human hypothalami from control, familial (FAD) and sporadic (SAD) AD patients (n = 1) in collaboration with the Brainbank of the University of Antioquia. RESULT: We identified presymptomatic transcriptomic changes in hypothalamic endothelial cells in 3xTg-AD mice. These changes were primarily observed at the capillary level and were related to immune and stress response. At 3-months, 3xTg-AD mice exhibited sex-specific metabolic alterations. While females showed significant increases in body weight, glucose levels, fat and pancreas mass, males exhibited significant decreases in the same parameters compared to WT mice. The pilot snRNAseq experiment with human samples was successful, obtaining ∼10000 nuclei/patient, comprising the different brain cell types, with large populations of neurons and oligodendrocytes identified. CONCLUSION: Our results reveal early transcriptomic changes in hypothalamic endothelial cells of 3xTg-AD mice, related to immune and stress responses. Furthermore, peripheral metabolic alterations were also observed at this stage, suggesting a sex-specific effect. We propose that hypothalamic dysfunction may drive these metabolic alterations and play a key role in AD. Further analyses are underway to confirm this association using mouse and human samples.
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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 | 0.000 |
| 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".