DAla2-GIP-GLU-PAL Protects Against Cognitive Deficits and Pathology in APP/PS1 Mice by Inhibiting Neuroinflammation and Upregulating cAMP/PKA/CREB Signaling Pathways

Article type: Research Article

Authors: Yuan, Li^{a; b} | Zhang, Jun^b | Guo, Jun-Hong^{c; *} | Holscher, Christian^d | Yang, Jun-Ting^b | Wu, Mei-Na^b | Wang, Zhao-Jun^b | Cai, Hong-Yan^e | Han, Ling-Na^a | Shi, Hui^b | Han, Yu-Fei^b | Qi, Jin-Shun^{b; *}

Affiliations: [a] Department of Physiology, Changzhi Medical College, Changzhi, Shanxi, PR China | [b] Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, PR China | [c] Department of Neurology, First Hospital, Shanxi Medical University, Taiyuan, Shanxi, PR China | [d] Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, Henan, PR China | [e] Department of Immunology and Microbiology, Shanxi Medical University, Taiyuan, Shanxi, PR China

Correspondence: [*] Correspondence to: Jinshun Qi, Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. Tel.: +86 351 413 5091; E-mail: [email protected]. Junhong Guo, Department of Neurology, First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. Tel.: +86 351 486 7014; E-mail: [email protected].

Abstract: Background:Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function. Type 2 diabetes mellitus (T2DM) is an important risk factor for AD. Glucose-dependent insulinotropic polypeptide (GIP) has been identified to be effective in T2DM treatment and neuroprotection. Objective:The present study investigated the neuroprotective effects and possible mechanisms of DAla2GIP-Glu-PAL, a novel long-lasting GIP analogue, in APP/PS1 AD mice. Methods:Multiple behavioral tests were performed to examine the cognitive function of mice. In vivo hippocampus late-phase long-term potentiation (L-LTP) was recorded to reflect synaptic plasticity. Immunohistochemistry and immunofluorescence were used to examine the Aβ plaques and neuroinflammation in the brain. IL-1β, TNF-α, and cAMP/PKA/CREB signal molecules were also detected by ELISA or western blotting. Results:DAla2GIP-Glu-PAL increased recognition index (RI) of APP/PS1 mice in novel object recognition test, elevated spontaneous alternation percentage of APP/PS1 mice in Y maze test, and increased target quadrant swimming time of APP/PS1 mice in Morris water maze test. DAla2GIP-Glu-PAL treatment enhanced in vivo L-LTP of APP/PS1 mice. DAla2GIP-Glu-PAL significantly reduced Aβ deposition, inhibited astrocyte and microglia proliferation, and weakened IL-1β and TNF-α secretion. DAla2GIP-Glu-PAL also upregulated cAMP/PKA/CREB signal transduction and inhibited NF-κB activation in the hippocampus of APP/PS1 mice. Conclusion:DAla2GIP-Glu-PAL can improve cognitive behavior, synaptic plasticity, and central pathological damage in APP/PS1 mice, which might be associated with the inhibition of neuroinflammation, as well as upregulation of cAMP-/PKA/CREB signaling pathway. This study suggests a potential benefit of DAla2GIP-Glu-PAL in the treatment of AD.

Keywords: Amyloid-β, cognitive behaviors, DAla2GIP-Glu-PAL, long-term synaptic plasticity, neuroinflammation

DOI: 10.3233/JAD-201262

Journal: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 695-713, 2021