Molecular Neurobiology

, Volume 54, Issue 8, pp 6074–6084 | Cite as

Linagliptin, a Dipeptidyl Peptidase-4 Inhibitor, Mitigates Cognitive Deficits and Pathology in the 3xTg-AD Mouse Model of Alzheimer’s Disease

  • Jayasankar Kosaraju
  • R. M. Damian Holsinger
  • Lixia Guo
  • Kin Yip TamEmail author


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.


Glucagon-like peptide-1 Glucose-dependent insulinotropic polypeptide Amyloid beta Tau phosphorylation Neuroinflammation 



We thank Shun Ming Yuen from Histopathology Core (Faculty of Health Sciences, University of Macau) for assistance in histological analysis and Shaolin Zhang for verifying the purity of linagliptin. We thank the Science and Technology Development Fund, Macao S.A. R (FDCT) (project reference no.: 118/2013/A3) for the financial support.

Authors’ Contribution

JK executed most of the study including dosing, behavioral studies, immunoblotting, histology, data interpretation, and manuscript writing. RMDH supported in analyzing the results and manuscript editing. LG involved in data interpretation. KYT supervised and guided all phases of the project, including the manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

12035_2016_125_MOESM1_ESM.tif (70 mb)
Fig S1 Cognitive assessment in 10 month old control (C57BL/6) and 3xTg-AD female mice in the Morris Water Maze test. (A) Latency to reach the escape platform and (B) path length taken to reach the platform during acquisition trials. (C) Percentage of time spent in the platform quadrant and (D) number of platform crossings during the probe trial. (E) Tracking details on day 4 trial 2 of corresponding groups. Significance was analyzed by unpaired t test (n = 6, mean ± SEM) using Graphpad Prism. **p < 0.01 and ***p < 0.001, compared to control mice (C57BL/6). (TIFF 71729 kb)
12035_2016_125_Fig10_ESM.gif (91 kb)

High resolution image (GIF 90 kb)

12035_2016_125_MOESM2_ESM.tif (39.1 mb)
Fig S2 Cognitive assessment in 10 month old control (C57BL/6) and 3xTg-AD female mice in the Y-maze test. (A) Time spent in the novel arm and (B) percentage of alterations. Significance was analyzed by unpaired t test (n = 6, mean ± SEM) using Graphpad Prism. ***p < 0.001, compared with control mice (C57BL/6). (TIFF 39998 kb)
12035_2016_125_Fig11_ESM.gif (52 kb)

High resolution image (GIF 51 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Jayasankar Kosaraju
    • 1
  • R. M. Damian Holsinger
    • 2
    • 3
  • Lixia Guo
    • 4
  • Kin Yip Tam
    • 1
    Email author
  1. 1.Drug Development Core, Faculty of Health SciencesUniversity of MacauTaipaChina
  2. 2.Laboratory of Molecular Neuroscience and Dementia, The Brain and Mind CentreThe University of SydneyCamperdownAustralia
  3. 3.The Discipline of Biomedical Science, School of Medical Sciences, Sydney Medical SchoolThe University of SydneyLidcombeAustralia
  4. 4.Chongqing Key Lab of Natural Medicine ResearchChongqing Technology and Business UniversityChongqingChina

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