Inhibiting 5-hydroxytryptamine receptor 3 alleviates pathological changes of a mouse model of Alzheimer's disease

Li Fen Liu, Yu Tong Liu, Dan Dan Wu, Jie Cheng, Na Na Li, Ya Ni Zheng, Liang Huang, Qiong Lan Yuan

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Extracellular amyloid beta (Aβ) plaques are main pathological feature of Alzheimer's disease. However, the specific type of neurons that produce Aβ peptides in the initial stage of Alzheimer's disease are unknown. In this study, we found that 5-hydroxytryptamin receptor 3A subunit (HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice (an Alzheimer's disease model) and patients with Alzheimer's disease. To investigate whether HTR3A-positive interneurons are associated with the production of Aβ plaques, we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aβ plaques in the mouse model. Some amyloid precursor protein-positive or β-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aβ plaques were co-localized with HTR3A interneurons. These results suggest that HTR3A -positive interneurons may partially contribute to the generation of Aβ peptides. We treated 5.0-5.5-month-old model mice with tropisetron, a HTR3 antagonist, for 8 consecutive weeks. We found that the cognitive deficit of mice was partially reversed, Aβ plaques and neuroinflammation were remarkably reduced, the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice. These findings suggest that HTR3A interneurons partly contribute to generation of Aβ peptide at the initial stage of Alzheimer's disease and inhibiting HTR3 partly reverses the pathological changes of Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)2019-2028
Number of pages10
JournalNeural Regeneration Research
Volume18
Issue number9
DOIs
StatePublished - Sep 2023

Keywords

  • 5-hydroxytryptamin receptor 3
  • Alzheimer's disease
  • HTR3 interneurons
  • amyloid beta plaques
  • calcineurin
  • cognitive deficits
  • iCa
  • nuclear factor of activated T-cells
  • transgenic amyloid precursor protein and presenilin-1 mice
  • tropisetron

ASJC Scopus subject areas

  • Developmental Neuroscience

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