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Basic Science and Pathogenesis.

Pablo Valderrama-Carmona1,2, Federico Pratesi1,2,3, Paule E H M'Bra1,2,3

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|December 24, 2025
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Summary
This summary is machine-generated.

Early Alzheimer's Disease (AD) stages show hypothalamic endothelial cell changes and sex-specific metabolic alterations in mice. Hypothalamic dysfunction may drive these metabolic changes, playing a key role in AD progression.

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Area of Science:

  • Neuroscience
  • Metabolic Regulation
  • Neurodegenerative Diseases

Background:

  • The hypothalamus regulates metabolism and energy homeostasis, linking the brain and peripheral tissues.
  • Alzheimer's Disease (AD) patients often display metabolic disturbances, suggesting hypothalamic involvement.
  • The role of the hypothalamus in AD pathogenesis remains largely unexplored.

Purpose of the Study:

  • To characterize early hypothalamic cellular and metabolic changes in a pre-symptomatic Alzheimer's Disease mouse model.
  • To investigate the potential link between hypothalamic dysfunction and metabolic alterations in AD.

Main Methods:

  • Single-cell RNA sequencing (scRNAseq) of hypothalami from 3-month-old WT and 3xTg-AD mice.
  • Analysis of body weight, blood glucose, body composition, and organ mass in 3xTg-AD mice.
  • Pilot single-nuclei RNA sequencing (snRNAseq) on post-mortem human hypothalami from AD patients.

Main Results:

  • Presymptomatic transcriptomic changes were identified in hypothalamic endothelial cells of 3xTg-AD mice, related to immune and stress responses.
  • 3xTg-AD mice exhibited sex-specific metabolic alterations at 3 months of age.
  • Female mice showed increased body weight and metabolic organ mass, while males showed decreased parameters compared to controls.

Conclusions:

  • Early transcriptomic alterations in hypothalamic endothelial cells occur in pre-symptomatic AD.
  • Sex-specific peripheral metabolic alterations are present at this early stage.
  • Hypothalamic dysfunction is proposed to drive metabolic alterations and play a critical role in Alzheimer's Disease.