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[P2–167]: NOVEL DUAL GLP‐1 AND GIP RECEPTOR ANALOG ATTENUATES HIGH‐FAT‐DIET‐INDUCED DISEASE PROGRESSION IN 3XTG‐AD MICE
Author(s) -
Kosaraju Jayasankar,
Tam Kin Yip,
Basavan Duraiswamy
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.06.818
Subject(s) - incretin , morris water navigation task , neuroprotection , neuroinflammation , agonist , medicine , endocrinology , dipeptidyl peptidase , cognitive decline , pharmacology , diabetes mellitus , type 2 diabetes , receptor , inflammation , biology , disease , hippocampus , dementia , biochemistry , enzyme
Background:Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are the incretin hormones shown to be active in the treatment of type-2 diabetes (T2D) and have also shown as efficacious in Alzheimer’s disease. Dipeptidyl peptidase-4 (DPP-4), an enzyme that is expressed in numerous cells rapidly inactivate endogenous GLP-1 and GIP. Therefore, DPP-4 resistant incretin analogs were developed as a therapeutic avenue to increase GLP-1 and GIP levels in the management of T2D. With this background, the present project is designed to examine the effectiveness of a dual agonist (called as DA-JC1) as a neuroprotective agent for the treatment of Alzheimer’s disease. Methods: Initially DA-JC1will be tested on cell culture models to determine their cytotoxicity, apoptosis and proliferation activity. To determine the therapeutic activity of DA-JC1 on Alzheimer’s disease, six month old 3xTg-ADmicewill be fed with high-fat diet for 6months and treated with dual agonist for 1month.After treatment,micewill be evaluated for cognitive ability on Morris Water Maze and Y-maze. Following cognitive evaluation mice will be sacrificed to determine the effect of the dual agonist (DA-JC1) on brain incretin levels, amyloid burden, tau phosphorylation and neuro-inflammation. Results: We confirm that DA-JC1 treatment for one month mitigates the cognitive deficits present in high-fat-diet fed 3xTg-AD mice. Moreover, DA-JC1 also improves brain incretin levels and attenuates amyloid beta, tau phosphorylation as well as neuroinflammation.Conclusions: In conclusion, DA-JC1 possesses neuroprotective properties that may be attributed to the improvement of incretin levels in the brain.