title: Linagliptin, a Dipeptidyl Peptidase-4 Inhibitor, Mitigates Cognitive Deficits and Pathology in the 3xTg-AD Mouse Model of Alzheimer's Disease.
abstract: Glucagon-like peptide-1 (GLP-1) is an incretin hormone shown to be active in the treatment of type-2 diabetes (T2D) and has also been shown as efficacious in Alzheimer's disease (AD). Dipeptidyl peptidase-4 (DPP-4), an enzyme that is expressed in numerous cells, rapidly inactivates endogenous GLP-1. Therefore, DPP-4 inhibition is employed as a therapeutic avenue to increase GLP-1 levels in the management of T2D. The effectiveness of DPP-4 inhibitors in the treatment of AD has been reported in various animal models of AD. With this background, the present study was designed to examine the effectiveness of linagliptin, a DPP-4 inhibitor in the 3xTg-AD mouse model of Alzheimer's disease. Nine-month-old 3xTg-AD mice were administered linagliptin orally (5, 10, and 20 mg/kg) for 8 weeks. At the end of the linagliptin treatment, mice were evaluated for cognitive ability on the Morris Water Maze and Y-maze. Following cognitive evaluation, mice were sacrificed to determine the effect of the linagliptin on brain incretin levels, amyloid burden, tau phosphorylation, and neuroinflammation. We confirm that linagliptin treatment for 8 weeks mitigates the cognitive deficits present in 3xTg-AD mice. Moreover, linagliptin also improves brain incretin levels and attenuates amyloid beta, tau phosphorylation as well as neuroinflammation. In conclusion, linagliptin possesses neuroprotective properties that may be attributed to the improvement of incretin levels in the brain.
authors.affiliation: Drug Development Core, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
authors.forename: Jayasankar
authors.initials: J
authors.lastname: Kosaraju
authors.affiliation: Laboratory of Molecular Neuroscience and Dementia, The Brain and Mind Centre, The University of Sydney, Camperdown, NSW, 2050, Australia.|The Discipline of Biomedical Science, School of Medical Sciences, Sydney Medical School, The University of Sydney, Lidcombe, NSW, 1875, Australia.
authors.forename: R M Damian
authors.initials: RMD
authors.lastname: Holsinger
authors.affiliation: Chongqing Key Lab of Natural Medicine Research, Chongqing Technology and Business University, Chongqing, 400067, China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Guo
authors.affiliation: Drug Development Core, Faculty of Health Sciences, University of Macau, Taipa, Macau, China. kintam@umac.mo.
authors.forename: Kin Yip
authors.initials: KY
authors.lastname: Tam
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000069476:Linagliptin / Q000494:pharmacology / Q000627:therapeutic use*; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D016875:tau Proteins; D000069476:Linagliptin; D052216:Glucagon-Like Peptide 1
keywords: Amyloid beta; Glucagon-like peptide-1; Glucose-dependent insulinotropic polypeptide; Neuroinflammation; Tau phosphorylation