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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\u20101 and GIP are incretin hormones that can ameliorate diabetes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In the present study, we tested the novel dual GLP\u20101\/GIP receptor agonist DA5\u2010CH in the icv. streptozotocin (STZ)\u2010induced insulin desensitization model of AD in rats to explore the protective effects of DA5\u2010CH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The results show that DA5\u2010CH could reverse the STZ\u2010induced working memory impairments in a Y\u2010maze tests, and spatial memory impairments in the water maze task, and decrease the levels of phosphorylated tau<jats:sup>S396<\/jats:sup> protein in the hippocampus. In EEG recordings, STZ treatment diminished the power of the theta band frequency. DA5\u2010CH was able to increase the energy of theta band activity in the hippocampal CA1 region. The drug also increased the expression of synapse\u2010related proteins in the hippocampus. After DA5\u2010CH treatment, mitochondrial stress was alleviated as shown by the improved ratio of Bax\/Bcl\u20102 in the hippocampus. Growth factor signaling was also normalized as shown by the increased level of the transcription factor P\u2010CREB<jats:sup>S133<\/jats:sup>. In addition, we were able to show that DA5\u2010CH can cross the blood\u2013brain barrier at an increased rate compared with other dual GLP\u20101\/GIP or single GLP\u20101 receptor agonists.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Therefore, our results demonstrate that DA5\u2010CH has neuroprotective effects in the STZ\u2010induced animal model and that DA5\u2010CH has potential to treat neurodegenerative disorders such as AD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/brb3.1505","type":"journal-article","created":{"date-parts":[[2020,1,21]],"date-time":"2020-01-21T04:11:11Z","timestamp":1579579871000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["The novel GLP\u20101\/GIP analogue DA5\u2010CH reduces tau phosphorylation and normalizes theta rhythm in the icv. 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