Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1
5-Year Impact Factor – 2.2
Scopus CiteScore – 3.4 (CiteScore Tracker 3.4)
Index Copernicus  – 161.11; MEiN – 140 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2020, vol. 29, nr 6, June, p. 661–668

doi: 10.17219/acem/121007

Publication type: original article

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

The role of GLP-1/GIP receptor agonists in Alzheimer’s disease

Chun Jiang Yu1,A,B,F, Dongying Ma2,A,B,E, Ling Ling Song3,B, Zhen Nan Zhai1,B, Ye Tao4,B,C, Ying Zhang5,B,C, Ling Yu Cai6,B,C, Ya Hui Hou7,B,D, Hong Yuan Chen1,B,E, Li Wang8,A,C

1 Department of Neurology, Second Affiliated Hospital of the Harbin Medical University, China

2 Department of Neurosurgery, Second Affiliated Hospital of the Harbin Medical University, China

3 Department of Neurology, Second Hospital of Chaoyang City, China

4 Department of Neurology, First Hospital of Suihua City, China

5 Department of Neurology, People’s Hospital of Hulunbuir, China

6 Department of Neurology, 117 hospital of PLA, Hangzhou, China

7 Department of Neurology, People’s Hospital of the West Coast New District of QingDao, China

8 Department of Geriatrics, Second Affiliated Hospital of the Harbin Medical University, China

Abstract

Background. New glucagon-like peptide-1 (GLP-1) analogues developed in recent years have a long half-life and offer further prospects for clinical application. At present, the neuroprotection of GLP-1 analogues in Alzheimer’s disease (AD) has just begun to be explored.
Objectives. To investigate how glucagon-like peptide-1 (liraglutide) plays a protective role in AD by regulating tau activation and BACE1 expression.
Material and Methods. Human neuroblastoma cell line SH-SY5Y cells were cultured in vitro and pretreated with different concentrations of liraglutide, and then treated with different concentrations of okadaic acid (OA) in order to observe the apoptosis of the SH-SY5Y cells. After liraglutide treatment, the apoptosis of neurons in AD rats was detected using flow cytometry, and tau activation and β-site APP cleaving enzyme 1 (BACE1) expression were detected using western blot.
Results. Different concentrations of OA were able to induce apoptosis of SH-SY5Y cells in a dose-dependent manner. Different concentrations of liraglutide were used to pretreat SH-SY5Y cells, which were able to protect the SH-SY5Y cells from apoptosis induced by OA. Okadaic acid significantly increased tau activation and BACE1 expression in the SH-SY5Y cells, which was blocked with liraglutide pretreatment. The results of a water maze experiment showed that liraglutide had significant protective effects on memory and cognitive ability in AD rats induced with OA, inhibited apoptosis of neural cells in AD rats, and inhibited tau activation and BACE1 expression of neural cells in AD rats induced with OA.
Conclusion. Liraglutide has a protective effect on AD in vivo and in vitro, which may be mediated by preventing neuronal apoptosis and inhibiting the activation of tau and the expression of BACE1.

Key words

Alzheimer’s disease, cognition, memory, nerve, glucagon-like peptide-1

References (24)

  1. Auti ST, Kulkarni YA. A systematic review on the role of natural products in modulating the pathways in Alzheimer’s disease. Int J Vitam Nutr Res. 2017;87(1–2):99–116.
  2. Alasmari F, Ashby CR Jr, Hall FS, Sari Y, Tiwari AK. Modulation of the ATP-binding cassette B1 transporter by neuro-inflammatory cytokines: Role in the pathogenesis of Alzheimer’s disease. Front Pharmacol. 2018;9:658.
  3. Voss T, Li J, Cummings J, et al. Randomized, controlled, proof-of-concept trial of MK-7622 in Alzheimer’s disease. Alzheimers Dement (N Y). 2018;4:173–181.
  4. Knezovic A, Osmanovic Barilar J, Babic A, et al. Glucagon-like peptide-1 mediates effects of oral galactose in streptozotocin-induced rat model of sporadic Alzheimer’s disease. Neuropharmacology. 2018;135:48–62.
  5. Li L. The molecular mechanism of glucagon-like peptide-1 therapy in Alzheimer’s disease, based on a mechanistic target of rapamycin pathway. CNS Drugs. 2017;31(7):535–549.
  6. Weisnagel SJ. The role of glucagon-like peptide-1 receptor agonists in cardiovascular disease prevention in type 2 diabetes mellitus: Evidence from the most recent clinical trials. Ann Transl Med. 2018;6(10):194.
  7. Athauda D, Foltynie T. The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson’s disease: Mechanisms of action. Drug Discov Today. 2016;21(5):802–818.
  8. Su JH, Anderson AJ, Cummings BJ, Cotman CW. Immunohistochemical evidence for apoptosis in Alzheimer’s disease. Neuroreport. 1994;5(18):2529–2533.
  9. Mandelkow EM, Mandelkow E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Med. 2012;2(7):a006247.
  10. Watkins GR, Wang N, Mazalouskas MD, et al. Monoubiquitination promotes calpain cleavage of the protein phosphatase 2A (PP2A) regulatory subunit α4, altering PP2A stability and microtubule-associated protein phosphorylation. J Biol Chem. 2012;287(29):24207–24215.
  11. Lee J, Hong H, Im J, Byun H, Kim D. The formation of PHF-1 and SMI-31 positive dystrophic neurites in rat hippocampus following acute injection of okadaic acid. Neurosci Lett. 2000;282(1–2):49–52.
  12. Goedert M, Jakes R, Qi Z, Wang JH, Cohen P. Protein phosphatase 2A is the major enzyme in brain that dephosphorylates tau protein phosphorylated by proline-directed protein kinases or cyclic AMP-dependent protein kinase. J Neurochem. 1995;65(6):2804–2807.
  13. Coimbra JRM, Marques DFF, Baptista SJ, et al. Highlights in BACE1 inhibitors for Alzheimer’s disease treatment. Front Chem. 2018;6:178.
  14. Wang P, Zheng X, Guo Q, et al. Systemic delivery of BACE1 siRNA through neuron-targeted nanocomplexes for treatment of ­Alzheimer’s disease. J Control Release. 2018;279:220–233.
  15. Andrew RJ, Fernandez CG, Stanley M, et al. Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2017;114(45):E9665–E9674.
  16. Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer’s disease. Nat Rev Dis Primers. 2015;1:15056.
  17. De-Paula VJ, Radanovic M, Diniz BS, Forlenza OV. Alzheimer’s disease. Subcell Biochem. 2012;65:329–352.
  18. Kim D, Su J, Cotman CW. Sequence of neurodegeneration and accumulation of phosphorylated tau in cultured neurons after okadaic acid treatment. Brain Res. 1999;839(2):253–262.
  19. Yoon S, Choi J, Yoon J, Huh JW, Kim D. Okadaic acid induces JNK activation, bim overexpression and mitochondrial dysfunction in cultured rat cortical neurons. Neurosci Lett. 2006;394(3):190–195.
  20. Cho MH, Kim DH, Choi JE, Chang EJ, Seung-Yongyoon. Increased phosphorylation of dynamin-related protein 1 and mitochondrial fission in okadaic acid-treated neurons. Brain Res. 2012;1454:100–110.
  21. Foidl BM, Humpel C. Differential hyperphosphorylation of tau-S199, -T231 and -S396 in organotypic brain slices of Alzheimer mice. A model to study early tau hyperphosphorylation using okadaic acid. Front Aging Neurosci. 2018;10:113.
  22. Vergallo A, Bun RS, Toschi N, et al. Association of cerebrospinal fluid α-synuclein with total and phospho-tau181 protein concentrations and brain amyloid load in cognitively normal subjective memory complainers stratified by Alzheimer’s disease biomarkers. Alzheimers Dement. 2018;14(12):1623–1631.
  23. Vassar R, Bennett BD, Babu-Khan S, et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999;286(5440):735–741.
  24. Coimbra JRM, Marques DFF, Baptista SJ, et al. Highlights in BACE1 inhibitors for Alzheimer’s disease treatment. Front Chem. 2018;6:178.
© Wroclaw Medical University