Related Experiment Video
Updated: Jul 6, 2025
Osmotic Minipump Implantation for Increasing Glucose Concentration in Mouse Cerebrospinal Fluid
Published on: April 7, 2023
DPP-4 inhibition by linagliptin ameliorates age-related mild cognitive impairment by regulating microglia
Fen Zhuge1, Liujie Zheng2, Yuxiang Pan2
1Institute of Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China.
Abstract:
Extensive preclinical evidence demonstrates a causative link between insulin signaling dysfunction and the pathogenesis of Alzheimer's disease (AD), and diabetic drugs may represent a promising approach to fighting AD. However, it remains to be determined which antidiabetic drugs are more effective in preventing cognitive impairment. Thus, the present study investigated the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on cognitive impairment in middle-aged mice by comparing it with the effect of metformin. We found that DPP-4 activity increased in the hippocampus of middle-aged mice, and DPP-4 was mainly expressed by microglia rather than astrocytes and oligodendrocytes. DPP-4 directly regulated M1/M2 microglia polarization following LPS or IL-4 stimulation, while DPP-4 inhibitor, linagliptin, suppressed M1-polarized activation and induced M2-polarized activation. Both linagliptin and metformin enhanced cognitive ability, increased hippocampal synaptic plasticity and neurogenesis, and decreased age-related oxidative stress and inflammation by regulating microglia polarization in the hippocampus of middle-aged mice. The combination of linagliptin and metformin showed a maximum protective effect compared to the individual drugs alone. Loss of macrophage inflammatory protein-1α (MIP-1α), a DPP-4 substrate, abrogated the cognitive protection and anti-inflammation effects of linagliptin. Therefore, the current investigation exhibits a potential utility for DPP-4 inhibition in attenuating microglia-mediated inflammation and preventing mild cognitive impairment (MCI) in middle-aged mice, and the effect was partly mediated by MIP-1α.
Insights
Dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin and metformin show promise in preventing cognitive impairment in middle-aged mice by reducing inflammation and oxidative stress, with a combined therapy offering maximum protection.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Insulin signaling dysfunction is linked to Alzheimer's disease (AD) pathogenesis.
- Diabetic drugs are being explored as a potential therapeutic strategy for AD.
- The comparative efficacy of different antidiabetic drugs in preventing cognitive decline is not well-established.
Purpose of the Study:
- To investigate the effect of the DPP-4 inhibitor linagliptin on cognitive impairment in middle-aged mice.
- To compare the efficacy of linagliptin with metformin in preventing cognitive decline.
- To elucidate the role of DPP-4 and its substrate MIP-1α in microglia-mediated inflammation and cognitive function.
Main Methods:
- Assessed cognitive ability, hippocampal synaptic plasticity, and neurogenesis in middle-aged mice treated with linagliptin and/or metformin.
- Investigated DPP-4 expression and activity in the hippocampus, focusing on microglia.
- Examined the impact of linagliptin on microglia polarization (M1/M2) and the role of MIP-1α.
Main Results:
- DPP-4 activity was elevated in the hippocampus of middle-aged mice, primarily in microglia.
- Linagliptin modulated microglia polarization from M1 to M2 phenotype.
- Both linagliptin and metformin improved cognitive function, enhanced synaptic plasticity and neurogenesis, and reduced oxidative stress and inflammation.
- Combined linagliptin and metformin treatment yielded the greatest protective effects.
- The cognitive and anti-inflammatory benefits of linagliptin were partly mediated by its substrate, MIP-1α.
Conclusions:
- DPP-4 inhibition, particularly with linagliptin, may be a viable strategy for mitigating microglia-mediated inflammation and preventing mild cognitive impairment (MCI).
- Linagliptin and metformin demonstrate neuroprotective effects by regulating microglia polarization and reducing neuroinflammation.
- Combined therapy with linagliptin and metformin offers synergistic benefits for cognitive health in aging mice.
More Related Videos
14:57Preparation of Acute Hippocampal Slices from Rats and Transgenic Mice for the Study of Synaptic Alterations during Aging and Amyloid Pathology
Published on: March 23, 2011
08:01Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits
Published on: March 16, 2016
