Neuroprotective and restorative properties of the GLP-1/GIP dual agonist DA-JC1 compared with a GLP-1 single agonist in Alzheimer's disease

The sister incretins glucagon-like peptide-1 (GLP-1) and glucagon dependent insulinotropic polypeptide (GIP) are growth factors responsible for re-sensitizing insulin signalling. Interestingly, their analogues, originally developed to treat type 2 diabetes (T2D), have demonstrated a range of neuroprotective and neurorestorative properties. Novel peptide GLP-1/GIP dual agonist (DA) shows good effects in diabetic patients, superior to the effects demonstrated by single GIP or GLP-1 mimetics. Furthermore, novel DAs have shown considerable neuroprotection in neurodegenerative models. Here, we investigated the neuroprotective and restorative involvement of the DA DA-JC1 and liraglutide (Lg), a single GLP-1 receptor analogue, in vitro using human neuroblastoma (SH-SY5Y) against oxidative stress induced by oxygen peroxide (H2O2), and in vivo, in a mouse model of Alzheimer's disease (AD), APP/PS1. First, we determined the ideal concentration of the peptides and demonstrated that DA-JC1 protects cells against oxidative stress more than Lg, improving cell viability, normalizing reactive oxygen species (ROS) and attenuating DNA damage generated by H2O2. Moreover, in 10-to-12-months-old APP/PS1 animals treated for 4 weeks, both Lg and DA-JC1 were very efficient in stimulating neurogenesis and reducing some important hallmarks of AD, but DA-JC1 was better than Lg in attenuating crucial neuroinflammatory markers, especially reactive astrocyte, in both wild-type (WT) and APP/PS1 hippocampal regions. Altogether, this study suggests an interactive role of GLP-1 and GIP receptors, enhancing the efficiency of single GLP-1 analogues, especially in attenuating oxidative stress and neuroinflammation. We confirm that combining GLP-1 and GIP results in a variety of beneficial effects, providing key evidences for the development of a promising therapeutic strategy for AD.