Recently multiple receptor agonists have been developed

Recently, multiple receptor agonists have been developed to treat type II diabetes (Finan et al., 2013, Finan et al., 2015). We have tested novel dual GLP-1/GIP receptor agonists that showed good neuroprotective effects that are superior to single GLP-1 analogues (Cao et al., 2016, Jalewa et al., 2017, Ji et al., 2016b, Yuan et al., 2017). The novel dual agonist DA3-CH was found to be superior to liraglutide in a mouse model of Parkinson’s disease (Yuan et al., 2017), demonstrating that the strategy of activating more than one incretin receptor type offers an advantage over single receptor agonists. Here, we show that a novel triple receptor agonist also shows promise as a potential treatment for AD, but further dose–response tests and direct comparisons with other drugs have to be conducted in order to evaluate if this new drug is superior to previous ones. GLP-1, GIP and glucagon are members of the growth factor family (Hölscher, 2016). Their respective receptors are classic 7-membrane spanning domain, G-protein coupled receptors that activate cAMP synthesis (Campbell and Drucker, 2013, Doyle and Egan, 2007, Holst et al., 2011). The activation of the second messenger cascade cAMP-PKA-CREB induces a number of cytoprotective processes, including the normalization of energy utilization, cell repair and growth-factor related gene expression (Holscher, 2014, Jalewa et al., 2016, Perry and Greig, 2004, Sharma et al., 2013). Importantly, GLP-1 and GIP also have anti-inflammatory properties. Astroglia and microglia express the receptors, and activating these reduce the inflammation response (Duffy and Holscher, 2013, Jalewa et al., 2017, Parthsarathy and Holscher, 2013, Spielman et al., 2017). Chronic inflammation is a main driver of neurodegenerative disorders, and a reduction of the inflammation in the vps34 shows protective effects (Akiyama et al., 2000, Clark et al., 2012, Lee et al., 2010). Based on the impressive preclinical data that demonstrate neuroprotection of such drugs, clinical trials have started that investigate the neuroprotective effects of the GLP-1 receptor agonists exendin-4 (Byetta, Bydureon®) and liraglutide (Victoza®) in patients with AD or with Parkinson disease (PD). A pilot study testing the GLP-1 analogue liraglutide in AD patients showed promising results. In a double blind, placebo controlled trial, AD patients showed no deterioration in brain activity as measured in the 18FDG-PET scan after 12 months of drug treatment. In contrast, the placebo group showed clear reductions in cortical activity as expected for this progressive neurodegenerative disease (Gejl et al., 2016). A phase II clinical trial is currently ongoing (Hölscher, 2016). A pilot trial testing exendin-4 in PD patients has shown good effects (NCT01174810). This open-label study tested the effects of exendin-4 in 45 patients. There were clear improvements in the motor coordination as shown in the MDS-UPDRS part 3 assessment, and cognition was improved as measured by the Mattis DRS-2 test battery that had been designed to evaluate cognitive impairments in PD patients (Aviles-Olmos et al., 2013). Patients were re-tested 12 months later, and the differences in motor performance and cognitive scores were still visible (Aviles-Olmos et al., 2014). A phase II double-blind, placebo controlled clinical trial that tested the once-weekly formulation of exendin-4, Bydureon®, confirmed the results of the pilot study. The drug group did not deteriorate in the MDS-UPDRS part 3 assessment after 48 weeks of treatment, and after 12 weeks of a wash-out period, the disease-modifying effect was still visible. In contrast, the placebo group deteriorated over time as would be expected in this disease (Athauda et al., 2017). In addition, a phase II trial testing liraglutide in PD patients has started, testing patients in a double blind, placebo controlled trial for one year (NCT02953665). A further clinical trial testing the GLP-1 receptor agonist Lixisenatide in PD patients is in planning.