A dual GLP-1 and Gcg receptor agonist rescues spatial memory and synaptic plasticity in APP/PS1 transgenic mice

Alzheimer's disease (AD) is a neurodegenerative disease that severely affects the health and lifespan of the elderly worldwide. Recently, the correlation between AD and type 2 diabetes mellitus (T2DM) has received intensive attention, and a promising new anti-AD strategy is the use of anti-diabetic drugs. Oxyntomodulin (Oxm) is a peptide hormone and growth factor that acts on neurons in the hypothalamus. OXM activates glucagon-like peptide 1 (GLP-1) and glucagon (Gcg) receptors, facilitates insulin signaling and has neuroprotective effects against Aβ_1-42-induced cytotoxicity in primary hippocampal neurons. Here, we tested the effects of the protease-resistant analogue (D-Ser2)Oxm on spatial memory and synaptic plasticity and the underlying molecular mechanisms in the APP/PS1 transgenic mouse model of AD. The results showed that (D-Ser2)Oxm not only alleviated the impairments of working memory and long-term spatial memory, but also reduced the number of Aβ plaques in the hippocampus, and reversed the suppression of hippocampal synaptic long-term potentiation (LTP). Moreover, (D-Ser2)Oxm administration significantly increased p-PI3K/p-AKT1 expression and decreased p-GSK3β levels in the hippocampus. These results are the first to show an in vivo neuroprotective role of (D-Ser2)Oxm in APP/PS1 mice, and this role involves the improvement of synaptic plasticity, clearance of Aβ and normalization of PI3K/AKT/GSK3β cell signaling in the hippocampus. This study suggests that (D-Ser2)Oxm holds promise for the prevention and treatment of AD.