Role of Insulin Receptor Substance-1 Modulating PI3K/Akt Insulin Signaling Pathway in Alzheimer's Disease

Overview

Journal 3 Biotech

Publisher Springer

Specialty Biotechnology

Date 2021 Apr 30

PMID 33927970

Citations 18

Authors

Mingcui Zheng

Pengwen Wang

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease, also regarded as "type 3 diabetes" for the last few years because of the brain insulin resistance (IR) and dysregulation of insulin signaling in the brain, which can further promote pathological progression of AD. IRS-1/PI3K/Akt insulin signaling pathway disorder and its downstream cascade reaction are responsible for cognitive decline in the brain. In recent years, a growing number of studies has documented that dysregulation of insulin signaling is a key feature of AD and has crucial correlations with serine/tyrosine (Ser/Tyr) phosphorylation of insulin receptor substance-1(IRS-1). Phosphorylation of this protein has been identified as an important molecule involved in the process of amyloid-β (Aβ) deposition into senile plaques (SPs) and tau hyperphosphorylation into neurofibrillary tangles (NFTs). In this paper, we review the links between IRS-1 and the PI3K/Akt insulin signaling pathway, and highlight phosphorylated IRS-1 which negatively regulated by downstream effector of Akt such as mTOR, S6K, and JNK, among others in AD. Furthermore, anti-diabetic drugs including metformin, thiazolidinediones, and glucagon-like peptide-1 (GLP-1) analogue could modulate IRS-1 phosphorylation, brain IR, PI3K/Akt insulin signaling pathway, and other pathologic processes of AD. The above suggest that anti-diabetic drugs may be promising strategies for AD disease-modifying treatments.

Citing Articles

Insights into the progressive impact of high-fat-diet induced insulin resistance on skeletal muscle and myocardium: A comprehensive study on C57BL6 mice.

Wang J, Dai L, Yu T, Xiao J PLoS One. 2025; 20(1):e0310458.

PMID: 39761309 PMC: 11703097. DOI: 10.1371/journal.pone.0310458.

Molecular Signaling Pathways of Quercetin in Alzheimer's Disease: A Promising Arena.

Alsaleem M, Al-Kuraishy H, Al-Gareeb A, Albuhadily A, Alrouji M, Yassen A Cell Mol Neurobiol. 2024; 45(1):8.

PMID: 39719518 PMC: 11668837. DOI: 10.1007/s10571-024-01526-w.

The double life of glucose metabolism: brain health, glycemic homeostasis, and your patients with type 2 diabetes.

Schwartz S, Herman M, Tun M, Barone E, Butterfield D BMC Med. 2024; 22(1):582.

PMID: 39696300 PMC: 11657227. DOI: 10.1186/s12916-024-03763-8.

mTOR Dysregulation, Insulin Resistance, and Hypertension.

Stanciu S, Jinga M, Miricescu D, Stefani C, Nica R, Stanescu-Spinu I Biomedicines. 2024; 12(8).

PMID: 39200267 PMC: 11351979. DOI: 10.3390/biomedicines12081802.

Effects of chronic treatment with metformin on brain glucose hypometabolism and central insulin actions in transgenic mice with tauopathy.

Hurtado-Carneiro V, LeBaut-Ayuso Y, Velazquez E, Flores-Lamas C, Fernandez-de la Rosa R, Garcia-Garcia L Heliyon. 2024; 10(15):e35752.

PMID: 39170185 PMC: 11337050. DOI: 10.1016/j.heliyon.2024.e35752.

References

Salameh T, Rhea E, Talbot K, Banks W . Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer's and Parkinson's disease therapeutics. Biochem Pharmacol. 2020; 180:114187. PMC: 7606641. DOI: 10.1016/j.bcp.2020.114187. View

Solmaz V, Cinar B, Yigitturk G, Cavusoglu T, Taskiran D, Erbas O . Exenatide reduces TNF-α expression and improves hippocampal neuron numbers and memory in streptozotocin treated rats. Eur J Pharmacol. 2015; 765:482-7. DOI: 10.1016/j.ejphar.2015.09.024. View

Jantrapirom S, Nimlamool W, Chattipakorn N, Chattipakorn S, Temviriyanukul P, Inthachat W . Liraglutide Suppresses Tau Hyperphosphorylation, Amyloid Beta Accumulation through Regulating Neuronal Insulin Signaling and BACE-1 Activity. Int J Mol Sci. 2020; 21(5). PMC: 7084306. DOI: 10.3390/ijms21051725. View

Talbot K . Brain insulin resistance in Alzheimer's disease and its potential treatment with GLP-1 analogs. Neurodegener Dis Manag. 2014; 4(1):31-40. PMC: 4465775. DOI: 10.2217/nmt.13.73. View

Boucher J, Kleinridders A, Kahn C . Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014; 6(1). PMC: 3941218. DOI: 10.1101/cshperspect.a009191. View

Fernando R, Albiston A, Chai S . The insulin-regulated aminopeptidase IRAP is colocalised with GLUT4 in the mouse hippocampus--potential role in modulation of glucose uptake in neurones?. Eur J Neurosci. 2008; 28(3):588-98. DOI: 10.1111/j.1460-9568.2008.06347.x. View

Gupta A, Bisht B, Dey C . Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer's-like changes. Neuropharmacology. 2011; 60(6):910-20. DOI: 10.1016/j.neuropharm.2011.01.033. View

Lanzerstorfer P, Yoneyama Y, Hakuno F, Muller U, Hoglinger O, Takahashi S . Analysis of insulin receptor substrate signaling dynamics on microstructured surfaces. FEBS J. 2015; 282(6):987-1005. DOI: 10.1111/febs.13213. View

Imfeld P, Bodmer M, Jick S, Meier C . Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study. J Am Geriatr Soc. 2012; 60(5):916-21. DOI: 10.1111/j.1532-5415.2012.03916.x. View

10.

Park K, Bowers W . Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Cell Signal. 2010; 22(7):977-83. PMC: 2860549. DOI: 10.1016/j.cellsig.2010.01.010. View

11.

Risner M, Saunders A, Altman J, Ormandy G, Craft S, Foley I . Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J. 2006; 6(4):246-54. DOI: 10.1038/sj.tpj.6500369. View

12.

Duarte A, Candeias E, Alves I, Mena D, Silva D, Machado N . Liraglutide Protects Against Brain Amyloid-β Accumulation in Female Mice with Early Alzheimer's Disease-Like Pathology by Partially Rescuing Oxidative/Nitrosative Stress and Inflammation. Int J Mol Sci. 2020; 21(5). PMC: 7084254. DOI: 10.3390/ijms21051746. View

13.

Velazquez R, Tran A, Ishimwe E, Denner L, Dave N, Oddo S . Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease. Neurobiol Aging. 2017; 58:1-13. PMC: 5819888. DOI: 10.1016/j.neurobiolaging.2017.06.003. View

14.

Perry T, Lahiri D, Chen D, Zhou J, Shaw K, Egan J . A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. J Pharmacol Exp Ther. 2002; 300(3):958-66. DOI: 10.1124/jpet.300.3.958. View

15.

Kleinridders A . Deciphering Brain Insulin Receptor and Insulin-Like Growth Factor 1 Receptor Signalling. J Neuroendocrinol. 2016; 28(11. PMC: 5129466. DOI: 10.1111/jne.12433. View

16.

. Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018; 18(1):88-106. PMC: 6291454. DOI: 10.1016/S1474-4422(18)30403-4. View

17.

Chiu S, Chen C, Cline H . Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008; 58(5):708-19. PMC: 3057650. DOI: 10.1016/j.neuron.2008.04.014. View

18.

Pardeshi R, Bolshette N, Gadhave K, Ahire A, Ahmed S, Cassano T . Insulin signaling: An opportunistic target to minify the risk of Alzheimer's disease. Psychoneuroendocrinology. 2017; 83:159-171. DOI: 10.1016/j.psyneuen.2017.05.004. View

19.

Chen W, Chen J, Liu Z, Luo B, Zhou T, Fei E . Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons. Brain Sci. 2020; 10(10). PMC: 7601223. DOI: 10.3390/brainsci10100706. View

20.

Yarchoan M, Arnold S . Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease. Diabetes. 2014; 63(7):2253-61. PMC: 4066335. DOI: 10.2337/db14-0287. View