Pimavanserin, a 5HT2A receptor inverse agonist, rapidly suppresses Aβ production and related pathology in a mouse model of Alzheimer's disease. Issue 5 (10th January 2021)

• Record Type: Journal Article
• Authors: Yuede, Carla M.; Wallace, Clare E.; Davis, Todd A.; Gardiner, Woodrow D.; Hettinger, Jane C.; Edwards, Hannah M.; Hendrix, Rachel D.; Doherty, Brookelyn M.; Yuede, Kayla M.; Burstein, Ethan S.; Cirrito, John R.
• Is Part Of: Journal of neurochemistry. Volume 156:Issue 5(2021)
• Page Start: 658
• Page End: 673
• Publication Date: 2021-01-10
• Subjects: 5HT2A receptors -- Alzheimer's disease -- amyloid‐β -- microdialysis -- Pimavanserin -- serotonin receptors; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15260
• Languages: English
• ISSNs: 0022-3042

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 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 . Abstract : (A) Pimavanserin (Pim) reduces activity at 5HT2A‐Rs which indirectly leads to activation of NMDARs (B). Calcium influx through NMDARs causes phosphorylation and activation of the extracellular regulated kinase (ERK) (C). ERK likely directly phosphorylates an α‐secretase protease which increases its enzymatic activity (D). An increase in non‐amyloidogenic processing of APP suppresses Aβ generation (E). Acute Pimavanserin causes a sustained 40% decrease in brain interstitial fluid Aβ levels of mice, whereas a chronic administration to aged APP/PS1 mice that already contain Aβ pathology causes a 30% decrease in Aβ plaques as well as improves several behavioral measures. This article has an Editorial Highlight, see https://doi.org/10.1111/jnc.15269