4.5 Editorial Material

Serotonin and amyloid deposition: A link between depression and Alzheimer's disease? An Editorial Highlight on Pimavanserin, a 5HT2A receptor inverse agonist, rapidly suppresses Aβ production and related pathology in a mouse model of Alzheimer's disease.

Journal

JOURNAL OF NEUROCHEMISTRY
Volume 156, Issue 5, Pages 560-562

Publisher

WILEY
DOI: 10.1111/jnc.15269

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Indirect agonism plays a role in the mechanism of antipsychotic action and in the pharmacological aspect of the serotonin drug pimavanserin. Treatments with pimavanserin and SSRIs have shown potential in reducing A beta deposition in transgenic Alzheimer's disease model mice, but further research is needed to understand the convergence of signaling pathways leading to A beta deposition.
Indirect agonism has been invoked as part of the mechanism of antipsychotic action at dopamine D-2/3 receptors, and more recently as a salient neuropharmacological aspect of the serotonin 5-HT2A drug pimavanserin (Pim). We now comment on an article in this volume showing that Pim treatment attenuates the deposition of A beta protein in brain of transgenic Alzheimer's disease model mice. Pim treatment may interfere with A beta deposition by shifting the balance between two 5-HT2A signaling pathways, that is, antagonism of G(q/11) signaling and agonism of G(alpha i1) signaling. Treatment with serotonin-selective reuptake inhibitors (SSRIs) evoked also reduced amyloid deposition in transgenic mice, but SSRI treatment does not unequivocally interfere in the progression of human Alzheimer's disease, perhaps because of complex effects of chronic SSRI treatment on multiple serotonin receptor types. Preclinical findings suggest Pim as a promising pharmacological strategy for intervening against Alzheimer's pathology, perhaps at a very early stage of the disease. However, much remains to be learned about the convergence of various receptor-mediated signaling pathways on the final common path leading to net A beta deposition.

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