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

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. Read the Editorial Highlight for this article on page 560.

• Authors: 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
• Journal: Journal of neurochemistry (J Neurochem) Vol. 156 Issue 5 Pg. 658-673 (03 2021) ISSN: 1471-4159 [Electronic] England
• PMID: 33278025 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 International Society for Neurochemistry.

Chemical References

• Amyloid beta-Peptides
• Piperidines
• Receptor, Serotonin, 5-HT2A
• Serotonin 5-HT2 Receptor Agonists
• Serotonin 5-HT2 Receptor Antagonists
• Urea
• pimavanserin

Topics

• Alzheimer Disease (drug therapy, genetics, metabolism, pathology)
• Amyloid beta-Peptides (antagonists & inhibitors, biosynthesis)
• Animals
• Drug Inverse Agonism
• Female
• Male
• Maze Learning (drug effects, physiology)
• Mice
• Mice, Inbred C3H
• Mice, Transgenic
• Piperidines (pharmacology, therapeutic use)
• Receptor, Serotonin, 5-HT2A (metabolism)
• Serotonin 5-HT2 Receptor Agonists (pharmacology, therapeutic use)
• Serotonin 5-HT2 Receptor Antagonists (pharmacology, therapeutic use)
• Urea (analogs & derivatives, pharmacology, therapeutic use)