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A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re-sensitizing insulin signaling in the Alzheimer icv. STZ rat model.
Behav Brain Res. 2017 06 01; 327:65-74.BB

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, accompanied by memory loss and cognitive impairments, and there is no effective treatment for it at present. Since type 2 diabetes (T2DM) has been identified as a risk factor for AD, the incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP), promising antidiabetic agents for the treatment of type 2 diabetes, have been tested in models of neurodegenerative disease including AD and achieved good results. Here we show for the first time the potential neuroprotective effect of a novel dual GLP-1/GIP receptor agonist (DA-JC4) in the icv. streptozotocin (STZ)-induced AD rat model. Treatment with DA-JC4 (10nmol/kg ip.) once-daily for 14days after STZ intracerebroventricular (ICV) administration significantly prevented spatial learning deficits in a Y- maze test and Morris water maze tests, and decreased phosphorylated tau levels in the rat cerebral cortex and hippocampus. DA-JC4 also alleviated the chronic inflammation response in the brain (GFAP-positive astrocytes, IBA1-positive microglia). Apoptosis was reduced as shown in the reduced ratio of pro-apoptotic BAX to anti- apoptotic Bcl-2 levels. Importantly, insulin signaling was re-sensitized as evidenced by a reduction of phospho-IRS1Ser1101 levels and phospho-AktSer473 up-regulation. In conclusion, the novel dual agonist DA-JC4 shows promise as a novel treatment for sporadic AD, and reactivating insulin signaling pathways may be a key mechanism that prevents disease progression in AD.

Authors+Show Affiliations

Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China.Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China.Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. Electronic address: linlilin999@163.com.Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK; Neurology Department, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, PR China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28342971

Citation

Shi, Lijuan, et al. "A Novel Dual GLP-1/GIP Receptor Agonist Alleviates Cognitive Decline By Re-sensitizing Insulin Signaling in the Alzheimer Icv. STZ Rat Model." Behavioural Brain Research, vol. 327, 2017, pp. 65-74.
Shi L, Zhang Z, Li L, et al. A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re-sensitizing insulin signaling in the Alzheimer icv. STZ rat model. Behav Brain Res. 2017;327:65-74.
Shi, L., Zhang, Z., Li, L., & Hölscher, C. (2017). A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re-sensitizing insulin signaling in the Alzheimer icv. STZ rat model. Behavioural Brain Research, 327, 65-74. https://doi.org/10.1016/j.bbr.2017.03.032
Shi L, et al. A Novel Dual GLP-1/GIP Receptor Agonist Alleviates Cognitive Decline By Re-sensitizing Insulin Signaling in the Alzheimer Icv. STZ Rat Model. Behav Brain Res. 2017 06 1;327:65-74. PubMed PMID: 28342971.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re-sensitizing insulin signaling in the Alzheimer icv. STZ rat model. AU - Shi,Lijuan, AU - Zhang,Zhihua, AU - Li,Lin, AU - Hölscher,Christian, Y1 - 2017/03/23/ PY - 2017/02/03/received PY - 2017/03/09/revised PY - 2017/03/21/accepted PY - 2017/3/28/pubmed PY - 2017/12/20/medline PY - 2017/3/27/entrez KW - Alzheimer’s disease KW - Apoptosis KW - Incretin KW - Inflammation KW - Insulin signaling KW - Tau phosphorylation KW - Type 2 diabetes mellitus SP - 65 EP - 74 JF - Behavioural brain research JO - Behav Brain Res VL - 327 N2 - Alzheimer's disease (AD) is a progressive neurodegenerative disorder, accompanied by memory loss and cognitive impairments, and there is no effective treatment for it at present. Since type 2 diabetes (T2DM) has been identified as a risk factor for AD, the incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP), promising antidiabetic agents for the treatment of type 2 diabetes, have been tested in models of neurodegenerative disease including AD and achieved good results. Here we show for the first time the potential neuroprotective effect of a novel dual GLP-1/GIP receptor agonist (DA-JC4) in the icv. streptozotocin (STZ)-induced AD rat model. Treatment with DA-JC4 (10nmol/kg ip.) once-daily for 14days after STZ intracerebroventricular (ICV) administration significantly prevented spatial learning deficits in a Y- maze test and Morris water maze tests, and decreased phosphorylated tau levels in the rat cerebral cortex and hippocampus. DA-JC4 also alleviated the chronic inflammation response in the brain (GFAP-positive astrocytes, IBA1-positive microglia). Apoptosis was reduced as shown in the reduced ratio of pro-apoptotic BAX to anti- apoptotic Bcl-2 levels. Importantly, insulin signaling was re-sensitized as evidenced by a reduction of phospho-IRS1Ser1101 levels and phospho-AktSer473 up-regulation. In conclusion, the novel dual agonist DA-JC4 shows promise as a novel treatment for sporadic AD, and reactivating insulin signaling pathways may be a key mechanism that prevents disease progression in AD. SN - 1872-7549 UR - https://www.unboundmedicine.com/medline/citation/28342971/A_novel_dual_GLP_1/GIP_receptor_agonist_alleviates_cognitive_decline_by_re_sensitizing_insulin_signaling_in_the_Alzheimer_icv__STZ_rat_model_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0166-4328(17)30224-3 DB - PRIME DP - Unbound Medicine ER -