Pimavanserin, A 5ht(2a) Receptor Inverse Agonist, Rapidly Suppresses A Beta Production And Related Pathology In A Mouse Model Of Alzheimer'S Disease

Amyloid-beta (A beta) 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 A beta generation, we postulated that 5HT(2A)-Rs may regulate A beta 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) A beta levels in real-time using in vivo microdialysis. Both compounds reduced ISF A beta levels by almost 50% within hours, but had no effect on A beta levels in 5HT(2A)-R knock-out mice. The A beta-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 A beta levels and A beta 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.