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

Feb 13, 2021Journal of Alzheimer's disease : JAD

DAla2-GIP-GLU-PAL may protect memory and brain health in Alzheimer's mice by reducing brain inflammation and boosting cell signaling

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Abstract

DAla2GIP-Glu-PAL treatment improved cognitive behavior and synaptic plasticity in APP/PS1 mice.

The recognition index increased in the novel object recognition test for APP/PS1 mice treated with DAla2GIP-Glu-PAL.
Spontaneous alternation percentage in the Y maze test improved for APP/PS1 mice receiving DAla2GIP-Glu-PAL.
Target quadrant swimming time increased in the Morris water maze test for APP/PS1 mice treated with DAla2GIP-Glu-PAL.
In vivo long-term potentiation was enhanced in APP/PS1 mice following DAla2GIP-Glu-PAL treatment.
DAla2GIP-Glu-PAL significantly reduced amyloid-beta deposition and inhibited the proliferation of astrocytes and microglia.
The treatment also upregulated signaling pathways associated with cAMP/PKA/CREB and inhibited NF-κB activation in the hippocampus.

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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.

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

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