Pimavanserin, a 5HT<sub>2A</sub> 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 Hendrix, Brookelyn M. Doherty, Kayla M. Yuede, Ethan S. Burstein, John R. Cirrito
Abstract
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 5HT 2A ‐Rs may regulate Aβ as well. We treated APP/PS1 transgenic mice with the selective 5HT 2A 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 5HT 2A ‐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. image Read the Editorial Highlight for this article on page 560 .