The novel GLP‐1/GIP analogue DA5‐CH reduces tau phosphorylation and normalizes theta rhythm in the icv. STZ rat model of AD

INTRODUCTION: Alzheimer's disease (AD) is the most common progressive neurodegenerative disease for which there is no cure. Recent studies have shown a close link between type 2 diabetes and AD, which suggested that drugs for type 2 diabetes may be effective for AD. GLP‐1 and GIP are incretin hormones that can ameliorate diabetes. METHODS: In the present study, we tested the novel dual GLP‐1/GIP receptor agonist DA5‐CH in the icv. streptozotocin (STZ)‐induced insulin desensitization model of AD in rats to explore the protective effects of DA5‐CH. RESULTS: The results show that DA5‐CH could reverse the STZ‐induced working memory impairments in a Y‐maze tests, and spatial memory impairments in the water maze task, and decrease the levels of phosphorylated tau(S396) protein in the hippocampus. In EEG recordings, STZ treatment diminished the power of the theta band frequency. DA5‐CH was able to increase the energy of theta band activity in the hippocampal CA1 region. The drug also increased the expression of synapse‐related proteins in the hippocampus. After DA5‐CH treatment, mitochondrial stress was alleviated as shown by the improved ratio of Bax/Bcl‐2 in the hippocampus. Growth factor signaling was also normalized as shown by the increased level of the transcription factor P‐CREB(S133). In addition, we were able to show that DA5‐CH can cross the blood–brain barrier at an increased rate compared with other dual GLP‐1/GIP or single GLP‐1 receptor agonists. CONCLUSION: Therefore, our results demonstrate that DA5‐CH has neuroprotective effects in the STZ‐induced animal model and that DA5‐CH has potential to treat neurodegenerative disorders such as AD.