A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re-sensitizing insulin signaling in the Alzheimer icv. STZ rat model.
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-IRS1Ser1101levels and phospho-AktSer473up-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.
Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China.
Lijuan
L
Shi
Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China.
Zhihua
Z
Zhang
Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. Electronic address: linlilin999@163.com.
Lin
L
Li
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.
Christian
C
Hölscher
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000502:physiology; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists* / Q000378:metabolism; D013311:Streptozocin; D016875:tau Proteins / Q000378:metabolism; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; C489131:Mapt protein, rat; D018696:Neuroprotective Agents; D010455:Peptides; D011964:Receptors, Gastrointestinal Hormone; D016875:tau Proteins; D013311:Streptozocin; C041086:gastric inhibitory polypeptide receptor; D051057:Proto-Oncogene Proteins c-akt; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
Alzheimer’s disease; Apoptosis; Incretin; Inflammation; Insulin signaling; Tau phosphorylation; Type 2 diabetes mellitus