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Liraglutide Suppresses Tau Hyperphosphorylation, Amyloid Beta Accumulation through Regulating Neuronal Insulin Signaling and BACE-1 Activity

Jantrapirom, Salinee, Nimlamool, Wutigri, Chattipakorn, Nipon, Chattipakorn, Siriporn, Temviriyanukul, Piya, Inthachat, Woorawee, Govitrapong, Piyarat, Potikanond, Saranyapin·2020·International Journal of Molecular Sciences
DOI 10.3390/ijms21051725PMC PMC7084306
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Abstract

Neuronal insulin resistance is a significant feature of Alzheimer’s disease (AD). Accumulated evidence has revealed the possible neuroprotective mechanisms of antidiabetic drugs in AD. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog and an antidiabetic agent, has a benefit in improving a peripheral insulin resistance. However, the neuronal effect of liraglutide on the model of neuronal insulin resistance with Alzheimer’s formation has not been thoroughly investigated. The present study discovered that liraglutide alleviated neuronal insulin resistance and reduced beta-amyloid formation and tau hyperphosphorylation in a human neuroblostoma cell line, SH-SY5Y. Liraglutide could effectively reverse deleterious effects of insulin overstimulation. In particular, the drug reversed the phosphorylation status of insulin receptors and its major downstream signaling molecules including insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and glycogen synthase kinase 3 beta (GSK-3β). Moreover, liraglutide reduced the activity of beta secretase 1 (BACE-1) enzyme, which then decreased the formation of beta-amyloid in insulin-resistant cells. This indicated that liraglutide can reverse the defect of phosphorylation status of insulin signal transduction but also inhibit the formation of pathogenic Alzheimer’s proteins like Aβ in neuronal cells. We herein provided the possibility that the liraglutide-based therapy may be able to reduce such deleterious effects caused by insulin resistance. In view of the beneficial effects of liraglutide administration, these findings suggest that the use of liraglutide may be a promising therapy for AD with insulin-resistant condition.

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  • The action of liraglutide regarding both Aβ production and alleviating insulin resistance has been shown to occur via reducing BACE1 activity.

    “The action of liraglutide regarding both Aβ production and alleviating insulin resistance has been shown to occur via reducing BACE1 activity.”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [169]

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Metadata

Authors
Jantrapirom, S., Nimlamool, W., Chattipakorn, N., Chattipakorn, S., Temviriyanukul, P., Inthachat, W., Govitrapong, P., & Potikanond, S.
Affiliations
  • Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
  • Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
  • Institute of Nutrition, Mahidol University, Salaya, Phuttamonthon, Nakhon Pathom 73170, Thailand
  • Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2020-03-03
Volume
21
Issue
5
Pages
1725
ISSN
1422-0067
DOI
10.3390/ijms21051725
PMC
PMC7084306
Cited by
60
References
9
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Thailand Research Fund (MRG6180078)
  • Faculty of Medicine, Chiang Mai University (85/2556)

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