{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T09:34:33Z","timestamp":1788341673488,"version":"build-2803163510"},"reference-count":54,"publisher":"SAGE Publications","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2021,3,23]]},"abstract":"<jats:p>Background: Alzheimer\u2019s 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 A\u03b2 plaques and neuroinflammation in the brain. IL-1\u03b2, TNF-\u03b1, 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 A\u03b2 deposition, inhibited astrocyte and microglia proliferation, and weakened IL-1\u03b2 and TNF-\u03b1 secretion. DAla2GIP-Glu-PAL also upregulated cAMP\/PKA\/CREB signal transduction and inhibited NF-\u03baB 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.<\/jats:p>","DOI":"10.3233\/jad-201262","type":"journal-article","created":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T22:29:09Z","timestamp":1613255349000},"page":"695-713","source":"Crossref","is-referenced-by-count":29,"title":["DAla2-GIP-GLU-PAL Protects Against Cognitive Deficits and Pathology in APP\/PS1 Mice by Inhibiting Neuroinflammation and Upregulating cAMP\/PKA\/CREB Signaling Pathways"],"prefix":"10.1177","volume":"80","author":[{"given":"Li","family":"Yuan","sequence":"first","affiliation":[{"name":"Department of Physiology, Changzhi Medical College, Changzhi, Shanxi, PR China"},{"name":"Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of 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