Semaglutide ameliorates Alzheimer's disease and restores oxytocin in APP/PS1 mice and human brain organoid models

Biomed Pharmacother. 2024 Nov:180:117540. doi: 10.1016/j.biopha.2024.117540. Epub 2024 Oct 13.

Abstract

Aims: To investigate the therapeutic effects and mechanisms of Semaglutide in Alzheimer's disease (AD), and identify its potential targets.

Methods: We systematically evaluated the effect of Semaglutide on Alzheimer's disease (AD), using both mice and human organoid models.

Results: Behavioral analyses on APP/PS1 mice demonstrated that Semaglutide improved the cognitive capabilities, particularly in the learning and memory domains. Biochemical investigations further highlighted its role in reducing amyloid plaque deposition and down-regulating the expression of glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) expression in the mouse brain tissues. Meanwhile, oxytocin (OXT) was up-regulated after Semaglutide treatment. Subsequent studies using human AD-brain organoids (BOs) models revealed that, upon Semaglutide treatment, these AD-BO models also exhibited reduced levels of amyloid-beta (Aβ), phosphorylated Tau (p-Tau) and GFAP expression as well as increased OXT level.

Conclusions: Semaglutide can ameliorate Alzheimer's disease in pre-clinical models, suggesting the promising therapeutic potential in AD patients.

Keywords: Alzheimer's Disease; Brain Organoid; Oxytocin; Semaglutide.

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Brain* / drug effects
  • Brain* / metabolism
  • Brain* / pathology
  • Cognition / drug effects
  • Disease Models, Animal*
  • Glucagon-Like Peptides* / pharmacology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic*
  • Organoids* / drug effects
  • Organoids* / metabolism
  • Oxytocin* / pharmacology
  • Plaque, Amyloid / drug therapy
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism

Substances

  • Glucagon-Like Peptides
  • semaglutide
  • Oxytocin
  • Amyloid beta-Protein Precursor
  • Presenilin-1
  • Amyloid beta-Peptides