| First Author | Yuede CM | Year | 2021 |
| Journal | J Neurochem | Volume | 156 |
| Issue | 5 | Pages | 658-673 |
| PubMed ID | 33278025 | Mgi Jnum | J:303677 |
| Mgi Id | MGI:6509528 | Doi | 10.1111/jnc.15260 |
| Citation | Yuede CM, et al. (2021) Pimavanserin, a 5HT2A receptor inverse agonist, rapidly suppresses Abeta production and related pathology in a mouse model of Alzheimer's disease. J Neurochem 156(5):658-673 |
| abstractText | Amyloid-beta (Abeta) 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 Abeta generation, we postulated that 5HT2A -Rs may regulate Abeta as well. We treated APP/PS1 transgenic mice with the selective 5HT2A inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) Abeta levels in real-time using in vivo microdialysis. Both compounds reduced ISF Abeta levels by almost 50% within hours, but had no effect on Abeta levels in 5HT2A -R knock-out mice. The Abeta-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 Abeta levels and Abeta 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. |
