Pimavanserin, a 5HT2A receptor inverse agonist, rapidly suppresses Aβ production and related pathology in a mouse model of Alzheimer’s disease

Carla M. Yuede, Clare E. Wallace, Todd A. Davis, Woodrow D. Gardiner, Jane C. Hettinger, Hannah M. Edwards, Rachel D. Hendrix, Brookelyn M. Doherty, Kayla M. Yuede, Ethan S. Burstein, John R. Cirrito

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Amyloid-β (Aβ) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer's disease (AD). Given that synaptic activity can regulate Aβ generation, we postulated that 5HT2A-Rs may regulate Aβ as well. We treated APP/PS1 transgenic mice with the selective 5HT2A inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) Aβ levels in real-time using in vivo microdialysis. Both compounds reduced ISF Aβ levels by almost 50% within hours, but had no effect on Aβ levels in 5HT2A-R knock-out mice. The Aβ-lowering effects of Pimavanserin were blocked by extracellular-regulated kinase (ERK) and NMDA receptor inhibitors. Chronic administration of Pimavanserin by subcutaneous osmotic pump to aged APP/PS1 mice significantly reduced CSF Aβ levels and Aβ pathology and improved cognitive function in these mice. Pimavanserin is FDA-approved to treat Parkinson's disease psychosis, and also has been shown to reduce psychosis in a variety of other dementia subtypes including Alzheimer's disease. These data demonstrate that Pimavanserin may have disease-modifying benefits in addition to its efficacy against neuropsychiatric symptoms of Alzheimer's disease. (Figure presented.). Read the Editorial Highlight for this article on page 560.

Original languageEnglish
Pages (from-to)658-673
Number of pages16
JournalJournal of Neurochemistry
Volume156
Issue number5
DOIs
StatePublished - Mar 2021

Keywords

  • 5HT receptors
  • Alzheimer's disease
  • Pimavanserin
  • amyloid-β
  • microdialysis
  • serotonin receptors

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