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

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.

Integrating Network Pharmacology, Molecular Docking and Pharmacological Evaluation for Exploring the Polyrhachis vicina Rogers in Ameliorating Depression

“…Studies showed that cAMP/PKA/CREB signaling pathway is closely related to glutamatergic synaptic plasticity. 28,29 As an important second messenger, cAMP can participate in the process of learning and memory and the changes of long-term synaptic plasticity. It can also activate cAMP-dependent protein kinase a (PKA), which can phosphorylate cAMP response element protein (CREB).…”

Electroacupuncture Enhances Neuroplasticity by Regulating the Orexin A-Mediated cAMP/PKA/CREB Signaling Pathway in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice

“…The cAMP/PKA/CREB signaling pathway is closely related to glutamate synaptic plasticity [41,42]. As an important second messenger, cAMP is involved in the process of learning and memory and changes in long-term synaptic plasticity.…”

Inhibition of phosphodiesterase‐4 in the spinal dorsal horn ameliorates neuropathic pain via cAMP‐cytokine‐Cx43 signaling in mice

“… 46 , 47 There are accumulating studies showing the regulatory role of PKA in TNF‐α. Increased PKA produces a reduction of TNF‐α expression in astrocytes and other cells in vitro and/or in vivo, 48 , 49 , 50 , 51 supporting that TNF‐α is a downstream target of cAMP‐PKA signaling, although it is not clear whether PKA directly or indirectly regulates TNF‐α.…”