A GLP-1/GIP Dual Receptor Agonist DA4-JC Effectively Attenuates Cognitive Impairment and Pathology in the APP/PS1/Tau Model of Alzheimer’s Disease¹

Article type: Research Article

Authors: Cai, Hong-Yan^{a; b; c; *} | Yang, Dan^a | Qiao, Jing^a | Yang, Jun-Ting^d | Wang, Zhao-Jun^{b; c; d} | Wu, Mei-Na^{b; c; d} | Qi, Jin-Shun^{b; c; d} | Hölscher, Christian^{e; *}

Affiliations: [a] Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, China | [b] Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, China | [c] Key Laboratory of Cellular Physiology, Shanxi Province, China | [d] Department of Physiology, Shanxi Medical University, Taiyuan, China | [e] Neuroscience Research Group, Henan University of Chinese Medicine, Zhengzhou, China

Correspondence: [*] Correspondence to: Hong-Yan Cai, PhD, Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, China. E-mail: [email protected]. and Christian Hölscher, PhD, Neuroscience Research Group, Henan University of Chinese Medicine, Zhengzhou, China. E-mail: [email protected].

Note: [1] This article received a correction notice (Erratum) with the reference: 10.3233/JAD-239006, available at http://doi.org/10.3233/JAD-239006.

Abstract: Background:Alzheimer’s disease (AD) is a degenerative disorder, accompanied by progressive cognitive decline, for which there is no cure. Recently, the close correlation between AD and type 2 diabetes mellitus (T2DM) has been noted, and a promising anti-AD strategy is the use of anti-T2DM drugs. Objective:To investigate if the novel glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist DA4-JC shows protective effects in the triple APP/PS1/tau mouse model of AD. Methods: A battery of behavioral tests were followed by in vivo recording of long-term potentiation (LTP) in the hippocampus, quantified synapses using the Golgi method, and biochemical analysis of biomarkers. Results:DA4-JC improved cognitive impairment in a range of tests and relieved pathological features of APP/PS1/tau mice, enhanced LTP in the hippocampus, increased numbers of synapses and dendritic spines, upregulating levels of post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), normalized volume and numbers of mitochondria and improving the phosphatase and tensin homologue induced putative kinase 1 (PINK1) - Parkin mitophagy signaling pathway, while downregulating amyloid, p-tau, and autophagy marker P62 levels. Conclusion:DA4-JC is a promising drug for the treatment of AD.

Keywords: Alzheimer’s disease, cognitive impairment, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, type 2 diabetes mellitus

DOI: 10.3233/JAD-210256

Journal: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 799-818, 2021