Research Progress on Neuroprotective Effects and Mechanisms of Glucagon-like Peptide 1 Analogues in Alzheimer's Disease

doi:10.12300/j.issn.1674-5817.2022.136

Abstract

Abstract:

Glucagon-like peptide 1 (GLP-1) is a kind of incretin produced in the intestinal with multiple pharmacological effects, which can stimulate insulin secretion effectively. Various GLP-1 analogues have been widely used in the treatment of type 2 diabetes mellitus. Alzheimer's disease (AD) is closely related to type 2 diabetes mellitus, with some common pathological features, such as insulin resistance, and epidemiological studies also showed that patients with type 2 diabetes mellitus have an increased risk of developing AD. GLP-1 analogues have shown beneficial effects in both preclinical animal research and clinical trials of AD. Therefore, the authors summarized the main characteristics of GLP-1 and AD, and analyzed the mechanisms of GLP-1 in preclinical AD studies of animal models. GLP-1 readily crosses the blood-brain barrier and exerts its neuroprotective effects by binding to and activating the widely distributed GLP-1 receptors (GLP-1Rs) in the brain, affecting multiple physiological and pathological processes including glucose metabolism, neuroinflammation, mitochondrial function, and cell proliferation. Insulin resistance and inflammation are key common pathways in AD and type 2 diabetes. GLP-1 may exert its neuroprotective effects by improving mitochondrial function and glycolysis, reducing oxidative stress levels, exerting anti-inflammatory and anti-apoptotic effects, inducing neurogenesis, and inhibiting glial cell proliferation. This paper maybe provide the reference for further study of GLP-1 analogues in AD, hoping to open new therapy venues for AD patients.

Key words: Glucagon-like peptide 1, Alzheimer's disease, Amyloid β-protein, Neuroprotective effect

CLC Number:

R-332

Chenghan MEI, Beibei CHEN. Research Progress on Neuroprotective Effects and Mechanisms of Glucagon-like Peptide 1 Analogues in Alzheimer's Disease[J]. Laboratory Animal and Comparative Medicine, 2023, 43(2): 186-193.

Figures/Tables 2

References 44

1	ARNOLD S E, ARVANITAKIS Z, MACAULEY-RAMBACH S L, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums[J]. Nat Rev Neurol, 2018, 14(3):168-181. DOI:10.1038/nrneurol.2017.185 .
2	BUTTERFIELD D A, HALLIWELL B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease[J]. Nat Rev Neurosci, 2019, 20(3):148-160. DOI:10.1038/s41583-019-0132-6 .
3	MCCLEAN P L, HÖLSCHER C. Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease[J]. Neuropharmacology, 2014, 76(Pt A):57-67. DOI:10.1016/j.neuropharm.2013.08.005 .
4	ZHENG J P, XIE Y Z, REN L J, et al. GLP-1 improves the supportive ability of astrocytes to neurons by promoting aerobic glycolysis in Alzheimer's disease[J]. Mol Metab, 2021, 47:101180. DOI:10.1016/j.molmet.2021.101180 .
5	LI T, JIAO J J, HÖLSCHER C, et al. A novel GLP-1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease[J]. Hippocampus, 2018, 28(5):358-372. DOI:10.1002/hipo.22837 .
6	CAO Y, HÖLSCHER C, HU M M, et al. DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer's disease[J]. Eur J Pharmacol, 2018, 827:215-226. DOI:10.1016/j.ejphar.2018.03.024 .
7	BATISTA A F, FORNY-GERMANO L, CLARKE J R, et al. The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease[J]. J Pathol, 2018, 245(1):85-100. DOI:10.1002/path.5056 .
8	WANG X H, WANG L, JIANG R R, et al. Exendin-4 antagonizes Aβ1-42-induced attenuation of spatial learning and memory ability[J]. Exp Ther Med, 2016, 12(5):2885-2892. DOI:10.3892/etm.2016.3742 .
9	CAI H Y, YANG D, QIAO J, et al. A GLP-1/GIP dual receptor agonist DA4-JC effectively attenuates cognitive impairment and pathology in the APP/PS1/tau model of Alzheimer's disease[J]. J Alzheimers Dis, 2021, 83(2):799-818. DOI:10.3233/JAD-210256 .
10	HÖLSCHER C. Potential role of glucagon-like peptide-1 (GLP-1) in neuroprotection[J]. CNS Drugs, 2012, 26(10):871-882. DOI:10.2165/11635890-000000000-00000 .
11	GRIECO M, GIORGI A, GENTILE M C, et al. Glucagon-like peptide-1: a focus on neurodegenerative diseases[J]. Front Neurosci, 2019, 13:1112. DOI:10.3389/fnins.2019.01112 .
12	HOLST J J. The physiology of glucagon-like peptide 1[J]. Physiol Rev, 2007, 87(4):1409-1439. DOI:10.1152/physrev. 00034.2006 .
13	ANDERSEN A, LUND A, KNOP F K, et al. Glucagon-like peptide 1 in health and disease[J]. Nat Rev Endocrinol, 2018, 14(7):390-403. DOI:10.1038/s41574-018-0016-2 .
14	DOYLE M E, EGAN J M. Mechanisms of action of glucagon-like peptide 1 in the pancreas[J]. Pharmacol Ther, 2007, 113(3):546-593. DOI:10.1016/j.pharmthera.2006.11.007 .
15	CALSOLARO V, EDISON P. Novel GLP-1 (glucagon-like peptide-1) analogues and insulin in the treatment for Alzheimer's disease and other neurodegenerative diseases[J]. CNS Drugs, 2015, 29(12):1023-1039. DOI:10.1007/s40263-015-0301-8 .
16	YILDIRIM SIMSIR I, SOYALTIN U E, CETINKALP S. Glucagon like peptide-1 (GLP-1) likes Alzheimer's disease[J]. Diabetes Metab Syndr, 2018, 12(3):469-475. DOI:10.1016/j.dsx.2018. 03.002 .
17	MÜLLER T D, et al. Glucagon-like peptide 1 (GLP-1)[J]. Mol Metab, 2019, 30:72-130. DOI:10.1016/j.molmet.2019.09.010 .
18	ATHAUDA D, FOLTYNIE T. The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson's disease: mechanisms of action[J]. Drug Discov Today, 2016, 21(5):802-818. DOI:10.1016/j.drudis.2016.01.013 .
19	BULGART H R, NECZYPOR E W, WOLD L E, et al. Microbial involvement in Alzheimer disease development and progression[J]. Mol Neurodegener, 2020, 15(1):42. DOI:10.1186/s13024-020-00378-4 .
20	MINTUN M A, LO A C, DUGGAN EVANS C, et al. Donanemab in early Alzheimer's disease[J]. N Engl J Med, 2021, 384(18):1691-1704. DOI:10.1056/NEJMoa2100708 .
21	LONG J M, HOLTZMAN D M. Alzheimer disease: an update on pathobiology and treatment strategies[J]. Cell, 2019, 179(2):312-339. DOI:10.1016/j.cell.2019.09.001 .
22	CASADESUS G, PUIG E R, WEBBER K M, et al. Targeting gonadotropins: an alternative option for Alzheimer disease treatment[J]. J Biomed Biotechnol, 2006, 2006(3):39508. DOI:10.1155/JBB/2006/39508 .
23	HAASS C, KAETHER C, THINAKARAN G, et al. Trafficking and proteolytic processing of APP[J]. Cold Spring Harb Perspect Med, 2012, 2(5): a006270. DOI:10.1101/cshperspect.a006270 .
24	PERRY T A, GREIG N H. A new Alzheimer's disease interventive strategy: GLP-1[J]. Curr Drug Targets, 2004, 5(6):565-571. DOI:10.2174/1389450043345245 .
25	CRARY J F, TROJANOWSKI J Q, SCHNEIDER J A, et al. Primary age-related tauopathy (PART): a common pathology associated with human aging[J]. Acta Neuropathol, 2014, 128(6):755-766. DOI:10.1007/s00401-014-1349-0 .
26	SHI Y, HOLTZMAN D M. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight[J]. Nat Rev Immunol, 2018, 18(12):759-772. DOI:10.1038/s41577-018-0051-1 .
27	GALE S C, GAO L, MIKACENIC C, et al. APOε4 is associated with enhanced in vivo innate immune responses in human subjects[J]. J Allergy Clin Immunol, 2014, 134(1): 127-34. DOI:10.1016/j.jaci.2014.01.032 .
28	MITTAL K, KATARE D P. Shared links between type 2 diabetes mellitus and Alzheimer's disease: a review[J]. Diabetes Metab Syndr Clin Res Rev, 2016, 10(2): S144-S149. DOI:10.1016/j.dsx.2016.01.021 .
29	BARBAGALLO M, DOMINGUEZ L J. Type 2 diabetes mellitus and Alzheimer's disease[J]. World J Diabetes, 2014,5(6):889-893. DOI: 10.4239/wjd.v5.i6.889 .
30	KELLAR D, CRAFT S. Brain insulin resistance in Alzheimer's disease and related disorders: mechanisms and therapeutic approaches[J]. Lancet Neurol, 2020, 19(9):758-766. DOI:10.1016/S1474-4422(20)30231-3 .
31	ARNOLD S E, ARVANITAKIS Z, MACAULEY-RAMBACH S L, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums[J]. Nat Rev Neurol, 2018, 14(3):168-181. DOI:10.1038/nrneurol.2017.185 .
32	LAWS S M, GASKIN S, WOODFIELD A, et al. Insulin resistance is associated with reductions in specific cognitive domains and increases in CSF tau in cognitively normal adults[J]. Sci Rep, 2017, 7(1):9766. DOI:10.1038/s41598-017-09577-4 .
33	BIUNDO F, DEL PRETE D, ZHANG H, et al. A role for tau in learning, memory and synaptic plasticity[J]. Sci Rep, 2018, 8(1):3184. DOI:10.1038/s41598-018-21596-3 .
34	FORNER S, BAGLIETTO-VARGAS D, MARTINI A C, et al. Synaptic impairment in Alzheimer's disease: a dysregulated symphony[J]. Trends Neurosci, 2017, 40(6):347-357. DOI:10.1016/j.tins.2017.04.002 .
35	MUSTAPIC M, TRAN J, CRAFT S, et al. Extracellular vesicle biomarkers track cognitive changes following intranasal insulin in Alzheimer's disease[J]. J Alzheimers Dis, 2019, 69(2):489-498. DOI:10.3233/JAD-180578 .
36	TALBOT K. Brain insulin resistance in Alzheimer's disease and its potential treatment with GLP-1 analogs[J]. Neurodegener Dis Manag, 2014, 4(1): 31-40. DOI:10.2217/nmt. 13.73 .
37	MCCLEAN P L, PARTHSARATHY V, FAIVRE E, et al. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease[J]. J Neurosci, 2011, 31(17):6587-6594. DOI:10.1523/JNEUROSCI.0529-11.2011 .
38	XIE Y Z, ZHENG J P, LI S Q, et al. GLP-1 improves the neuronal supportive ability of astrocytes in Alzheimer's disease by regulating mitochondrial dysfunction via the cAMP/PKA pathway[J]. Biochem Pharmacol, 2021, 188:114578. DOI:10.1016/j.bcp.2021.114578 .
39	HÖLSCHER C. Insulin signaling impairment in the brain as a risk factor in Alzheimer's disease[J]. Front Aging Neurosci, 2019, 11:88. DOI:10.3389/fnagi.2019.00088 .
40	CHEN S, YIN L, XU Z, et al. Inhibiting receptor for advanced glycation end product (AGE) and oxidative stress involved in the protective effect mediated by glucagon-like peptide-1 receptor on AGE induced neuronal apoptosis[J]. Neurosci Lett, 2016, 612:193-198. DOI:10.1016/j.neulet.2015.12.007 .
41	DAY S M, YANG W Z, WANG X, et al. Glucagon-like peptide-1 cleavage product improves cognitive function in a mouse model of down syndrome[J]. eNeuro, 2019, 6(2): ENEURO. 0031-ENEURO.0019.2019. DOI:10.1523/ENEURO.0031-19.2019 .
42	OZBEN T, OZBEN S. Neuro-inflammation and anti-inflammatory treatment options for Alzheimer's disease[J]. Clin Biochem, 2019, 72:87-89. DOI:10.1016/j.clinbiochem. 2019. 04.001 .
43	LIU X Y, ZHANG N, ZHANG S X, et al. Potential new therapeutic target for Alzheimer's disease: Glucagon-like peptide-1[J]. Eur J Neurosci, 2021, 54(10):7749-7769. DOI:10.1111/ejn.15502 .
44	ROWLANDS J, HENG J L, NEWSHOLME P, et al. Pleiotropic effects of GLP-1 and analogs on cell signaling, metabolism, and function[J]. Front Endocrinol (Lausanne), 2018, 9:672. DOI:10.3389/fendo.2018.00672 .

药物 Drug	动物 Animal	给药前月龄或体质量 Age or body mass before dosing	给药方式及剂量 Dosage and Administration	给药周期 Dosing intervals	行为学实验 Behavioural experiments	结论 Conclusions
利拉鲁肽 Liraglutide^[3]	APP/PS1小鼠（♂）	14月龄	ip，25 nmol/kg体质量	qd，连续2月	新物体识别、水迷宫	逆转记忆损害
利拉鲁肽 Liraglutide^[4]	5xFAD小鼠（♂）	4月龄	ih，25 nmol/kg体质量	qd，连续2月	水迷宫	改善认知
GLP-1/GIP/Gcg triagonist^[5]	3xTg-AD小鼠（♂/♀）	7月龄	ip，10 nmol/kg体质量	qd，连续30 d	旷场、Y迷宫、水迷宫	改善长期空间记忆和工作记忆
GLP-1/GIP dual agonist DA5-CH^[6]	APP/PS1小鼠（♂/♀）	9月龄	ip，10 nmol/kg体质量	qd，连续28 d	旷场、Y迷宫、水迷宫	改善工作记忆和长期空间记忆
利拉鲁肽 Liraglutide^[7]	Swiss小鼠（脑室内注射Aβ寡聚物，♂）	3月龄	ip，25 nmol/kg体质量	qd，连续7 d	新物体识别、对象位置记忆模型	可逆转Aβ寡聚物引起的记忆障碍
艾塞那肽Exendin-4^[8]	SD大鼠（海马内微量注射Aβ1–42，♂）	220~260 g	海马内微量注射， 0.2 nmol（1 µL）	单次	水迷宫	显著拮抗Aβ片段引起的空间学习和记忆能力损害
GLP-1/GIP dual agonist DA4-JC^[9]	3xTg-AD小鼠（♂/♀）	8月龄	ip，10 nmol/kg体质量	qd，连续46 d	旷场、新物体识别、Y迷宫、水迷宫	改善认知

药物 Drug	动物 Animal	给药前月龄或体质量 Age or body mass before dosing	给药方式及剂量 Dosage and Administration	给药周期 Dosing intervals	行为学实验 Behavioural experiments	结论 Conclusions
利拉鲁肽 Liraglutide^[3]	APP/PS1小鼠（♂）	14月龄	ip，25 nmol/kg体质量	qd，连续2月	新物体识别、水迷宫	逆转记忆损害
利拉鲁肽 Liraglutide^[4]	5xFAD小鼠（♂）	4月龄	ih，25 nmol/kg体质量	qd，连续2月	水迷宫	改善认知
GLP-1/GIP/Gcg triagonist^[5]	3xTg-AD小鼠（♂/♀）	7月龄	ip，10 nmol/kg体质量	qd，连续30 d	旷场、Y迷宫、水迷宫	改善长期空间记忆和工作记忆
GLP-1/GIP dual agonist DA5-CH^[6]	APP/PS1小鼠（♂/♀）	9月龄	ip，10 nmol/kg体质量	qd，连续28 d	旷场、Y迷宫、水迷宫	改善工作记忆和长期空间记忆
利拉鲁肽 Liraglutide^[7]	Swiss小鼠（脑室内注射Aβ寡聚物，♂）	3月龄	ip，25 nmol/kg体质量	qd，连续7 d	新物体识别、对象位置记忆模型	可逆转Aβ寡聚物引起的记忆障碍
艾塞那肽Exendin-4^[8]	SD大鼠（海马内微量注射Aβ1–42，♂）	220~260 g	海马内微量注射， 0.2 nmol（1 µL）	单次	水迷宫	显著拮抗Aβ片段引起的空间学习和记忆能力损害
GLP-1/GIP dual agonist DA4-JC^[9]	3xTg-AD小鼠（♂/♀）	8月龄	ip，10 nmol/kg体质量	qd，连续46 d	旷场、新物体识别、Y迷宫、水迷宫	改善认知

[1]	. Guidelines for the Selection of Animal Models and Preclinical Drug Trials for Spontaneous Intracerebral Hemorrhage (2024 Edition) [J]. Laboratory Animal and Comparative Medicine, 2024, (): 1-28.
[2]	Committee of Experts on Medical Animal Experiments, Chinese Research Hospital Association. Guidelines for the Selection of Animal Models and Preclinical Drug Trials for Spontaneous Intracerebral Hemorrhage (2024 Edition) [J]. Laboratory Animal and Comparative Medicine, 2024, 44(1): 3-30.
[3]	Tianwei LIANG, Yasheng DENG, Hui HUANG, Na RONG, Xin LIU, Yujie WANG, Jiang LIN. Preparation Methods and Evaluation Criteria Analysis of Animal Models for Perimenopausal Syndrome [J]. Laboratory Animal and Comparative Medicine, 2024, 44(1): 74-84.
[4]	Tingting FENG, Yitong LI, Yue WU, Jue WANG, Qi KONG. Transcriptome Data and Comparative Medical Analysis of COVID-19 Virus Infection [J]. Laboratory Animal and Comparative Medicine, 2024, 44(1): 62-73.
[5]	Yishu LIU, Shanmin ZHAO, Liping CAI. Application and Comparison of Different Anesthetic Ventilation Methods in Minimally Invasive Thoracic Surgery Training [J]. Laboratory Animal and Comparative Medicine, 2024, 44(1): 97-104.
[6]	Zhengwen MA, Xiaying LI, Xiaoyu LIU, Yao LI, Jian WANG, Jin LU, Guoyuan CHEN, Xiao LU, Yu BAI, Xuancheng LU, Yonggang LIU, Wanyong PANG, Yufeng TAO. Interpretation and Elaboration for the ARRIVE Guidelines 2.0—Animal Research: Reporting In Vivo Experiments (V) [J]. Laboratory Animal and Comparative Medicine, 2024, 44(1): 105-114.
[7]	. [J]. Laboratory Animal and Comparative Medicine, 2024, 44(1): 121-126.
[8]	Qianqian TANG, Xiuli ZHANG, Zai CHANG. Statistical Analysis of the Leakage Situation in the Automated Watering System for Mice in Tsinghua University Laboratory Animal Resources Center [J]. Laboratory Animal and Comparative Medicine, 2024, 44(1): 85-91.
[9]	. [J]. Laboratory Animal and Comparative Medicine, 2024, 44(1): 115-120.
[10]	Xiaying LI, Yonglu TIAN, Xiaoyu LIU, Xuancheng LU, Guoyuan CHEN, Xiao LU, Yu BAI, Jing GAO, Yao LI, Yusheng WEI, Wanyong PANG, Yufeng TAO. Explanation and Elaboration for the ARRIVE Guidelines 2.0—Reporting Animal Research and In Vivo Experiments (Ⅳ) [J]. Laboratory Animal and Comparative Medicine, 2023, 43(6): 659-668.
[11]	Jiaoxiang WANG, Yan WANG, Ke HU, Kaixiang XU, Taiyun WEI, Deling JIAO, Heng ZHAO, Hongye ZHAO, HongJiang WEI. Establishment of PCR Identification Method for Pig Blood Type [J]. Laboratory Animal and Comparative Medicine, 2023, 43(6): 585-594.
[12]	Shuo WANG, Yunhui LÜ, Xiaokang WANG, Zhenhao ZHANG, Yongchun CUI. Construction and Verification of Quality Evaluation Indicator System for Extracorporeal Membrane Oxygenation Animal Experimental Platform [J]. Laboratory Animal and Comparative Medicine, 2023, 43(6): 604-611.
[13]	Dan WANG, Xiaolu ZHANG, Yan WANG, Bo FU, Wendong WANG, Jing LIU, Suyin ZHANG, Yihe WU, Deguo WU, Xiaoyan DU, Dawei ZHAN, Xiulin ZHANG, Changlong LI. Study on the Antibody Production Efficiency in Modified Big-BALB/c Mice [J]. Laboratory Animal and Comparative Medicine, 2023, 43(6): 612-618.
[14]	Jinhuan MIAO, Xia XU, Lu ZHOU, Haiyan CHENG, Yan HE. Visual Analysis of Animal Experiments on Traditional Chinese Medicine (TCM) Nursing Technology Based on VOSviewer [J]. Laboratory Animal and Comparative Medicine, 2023, 43(6): 626-635.
[15]	Yinghan WAN, Yexin GU, Yunong YUAN, Min TANG, Li LU. Implications on the Development of Animal Disease Models from FDA Modernization Act 2.0 [J]. Laboratory Animal and Comparative Medicine, 2023, 43(5): 472-481.