Chronic 5-HT4 receptor activation decreases Aß production and deposition in hAPP/PS1 mice.

Lowering the production and accumulation of Aß has been explored as treatment for Alzheimer's disease (AD), because Aß is postulated to play an important role in the pathogenesis of AD. 5-HT4 receptors are an interesting drug target in this regard, as their activation might stimulate α-secretase processing, which increases sAPPα and reduces Aß, at least according to the central dogma in APP processing. Here we describe a novel high-affinity 5-HT4 receptor agonist SSP-002392 that, in cultured human neuroblastoma cells, potently increases the levels of cAMP and sAPPα at 100-fold lower concentrations than the effective concentrations of prucalopride, a known selective 5-HT4 receptor agonist. Chronic administration of this compound in a hAPP/PS1 mouse model of Alzheimer's disease decreased soluble and insoluble Aß in hippocampus, but the potential mechanisms underlying these observations seem to be complex. We found no evidence for direct α-secretase stimulation in the brain in vivo, but observed decreased APP and BACE-1 expression and elevated astroglia and microglia responses. Taken together these results provide support for a potential disease-modifying aspect when stimulating central 5-HT4 receptors; however, the complexity of the phenomena warrants further research.

ß-arrestin 2 regulates Aß generation and γ-secretase activity in Alzheimer's disease.

ß-arrestins are associated with numerous aspects of G protein-coupled receptor (GPCR) signaling and regulation and accordingly influence diverse physiological and pathophysiological processes. Here we report that ß-arrestin 2 expression is elevated in two independent cohorts of individuals with Alzheimer's disease. Overexpression of ß-arrestin 2 leads to an increase in amyloid-ß (Aß) peptide generation, whereas genetic silencing of Arrb2 (encoding ß-arrestin 2) reduces generation of Aß in cell cultures and in Arrb2(-/-) mice. Moreover, in a transgenic mouse model of Alzheimer's disease, genetic deletion of Arrb2 leads to a reduction in the production of Aß(40) and Aß(42). Two GPCRs implicated previously in Alzheimer's disease (GPR3 and the ß(2)-adrenergic receptor) mediate their effects on Aß generation through interaction with ß-arrestin 2. ß-arrestin 2 physically associates with the Aph-1a subunit of the γ-secretase complex and redistributes the complex toward detergent-resistant membranes, increasing the catalytic activity of the complex. Collectively, these studies identify ß-arrestin 2 as a new therapeutic target for reducing amyloid pathology and GPCR dysfunction in Alzheimer's disease.