8-weeks Aerobic Exercise Ameliorates Cognitive Deficit and Mitigates Ferroptosis Triggered by Iron Overload in the Prefrontal Cortex of / Mice Through Xc/GPx4 Pathway

Overview

Journal Front Neurosci

Date 2024 Sep 24

PMID 39315073

Authors

Chaoyang Li

Kaiyin Cui

Xinyuan Zhu

Shufan Wang

Qing Yang

Guoliang Fang

Affiliations

Soon will be listed here.

Abstract

Background: Alzheimer's disease (AD) is a degenerative disorder of the central nervous system characterized by notable pathological features such as neurofibrillary tangles and amyloid beta deposition. Additionally, the significant iron accumulation in the brain is another important pathological hallmark of AD. Exercise can play a positive role in ameliorating AD, but the mechanism is unclear. The purpose of the study is to explore the effect of regular aerobic exercise iron homeostasis and lipid antioxidant pathway regarding ferroptosis in the prefrontal cortex (PFC) of / (APP/PS1) mice.

Methods: Eighty 6-month-old C57BL/6 J and APP/PS1 mice were divided equally into 8-weeks aerobic exercise groups and sedentary groups. Subsequently, Y-maze, Morris water maze test, iron ion detection by probe, Western Blot, ELISA, RT-qPCR, HE, Nissle, Prussian Blue, IHC, IF, and FJ-C staining experiments were conducted to quantitatively assess the behavioral performance, iron levels, iron-metabolism-related proteins, lipid antioxidant-related proteins and morphology in each group of mice.

Results: In APP/PS1 mice, the increase in heme input proteins and heme oxygenase lead to the elevated levels of free iron in the PFC. The decrease in ferritin content by ferritin autophagy fails to meet the storage needs for excess free iron within the nerve cells. Ultimately, the increase of free ferrous iron triggers the Fenton reaction, may lead to ferroptosis and resulting in cognitive impairment in APP/PS1 mice. However, 8-weeks aerobic exercise induce upregulation of the Xc/GPx4 pathway, which can reverse the lipid peroxidation process, thereby inhibiting ferroptosis in APP/PS1 mice.

Conclusion: 8 weeks aerobic exercise can improve learning and memory abilities in AD, upregulate GPx4/Xc pathway in PFC to reduce ferroptosis induced by AD.

Citing Articles

Physical Activity Reduces Metabolic Risk via Iron Metabolism: Cross-National Evidence Using the Triglyceride-Glucose Index.

Hao Z, Guo X, Wang Y, Yang G Metabolites. 2024; 14(12).

PMID: 39728432 PMC: 11676255. DOI: 10.3390/metabo14120651.

References

Pootrakul P, Breuer W, Sametband M, Sirankapracha P, Hershko C, Cabantchik Z . Labile plasma iron (LPI) as an indicator of chelatable plasma redox activity in iron-overloaded beta-thalassemia/HbE patients treated with an oral chelator. Blood. 2004; 104(5):1504-10. DOI: 10.1182/blood-2004-02-0630. View

Koo J, Kang E . Effects of treadmill exercise on the regulatory mechanisms of mitochondrial dynamics and oxidative stress in the brains of high-fat diet fed rats. J Exerc Nutrition Biochem. 2019; 23(1):28-35. PMC: 6477818. DOI: 10.20463/jenb.2019.0005. View

Xia J, Li B, Yin L, Zhao N, Yan Q, Xu B . Treadmill exercise decreases β-amyloid burden in APP/PS1 transgenic mice involving regulation of the unfolded protein response. Neurosci Lett. 2019; 703:125-131. DOI: 10.1016/j.neulet.2019.03.035. View

Huang Y, Mucke L . Alzheimer mechanisms and therapeutic strategies. Cell. 2012; 148(6):1204-22. PMC: 3319071. DOI: 10.1016/j.cell.2012.02.040. View

Chiabrando D, Fiorito V, Petrillo S, Tolosano E . Unraveling the Role of Heme in Neurodegeneration. Front Neurosci. 2018; 12:712. PMC: 6189481. DOI: 10.3389/fnins.2018.00712. View

Jiang D, Li X, Williams R, Patel S, Men L, Wang Y . Ternary complexes of iron, amyloid-beta, and nitrilotriacetic acid: binding affinities, redox properties, and relevance to iron-induced oxidative stress in Alzheimer's disease. Biochemistry. 2009; 48(33):7939-47. PMC: 2757041. DOI: 10.1021/bi900907a. View

Choi S, Bylykbashi E, Chatila Z, Lee S, Pulli B, Clemenson G . Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model. Science. 2018; 361(6406). PMC: 6149542. DOI: 10.1126/science.aan8821. View

Chen J, Zhu T, Yu D, Yan B, Zhang Y, Jin J . Moderate Intensity of Treadmill Exercise Rescues TBI-Induced Ferroptosis, Neurodegeneration, and Cognitive Impairments via Suppressing STING Pathway. Mol Neurobiol. 2023; 60(9):4872-4896. PMC: 10415513. DOI: 10.1007/s12035-023-03379-8. View

Sahlstedt L, Ebeling F, von Bonsdorff L, Parkkinen J, Ruutu T . Non-transferrin-bound iron during allogeneic stem cell transplantation. Br J Haematol. 2001; 113(3):836-8. DOI: 10.1046/j.1365-2141.2001.02820.x. View

10.

Choi Y, Kim Y . Beneficial and Detrimental Roles of Heme Oxygenase-1 in the Neurovascular System. Int J Mol Sci. 2022; 23(13). PMC: 9266949. DOI: 10.3390/ijms23137041. View

11.

WALLING C, Partch R, Weil T . Kinetics of the decomposition of hydrogen peroxide catalyzed by ferric ethylenediaminetetraacetate complex. Proc Natl Acad Sci U S A. 1975; 72(1):140-2. PMC: 432257. DOI: 10.1073/pnas.72.1.140. View

12.

Wakhloo D, Scharkowski F, Curto Y, Butt U, Bansal V, Steixner-Kumar A . Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin. Nat Commun. 2020; 11(1):1313. PMC: 7062779. DOI: 10.1038/s41467-020-15041-1. View

13.

Xiao Y, Ma B, McElheny D, Parthasarathy S, Long F, Hoshi M . Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease. Nat Struct Mol Biol. 2015; 22(6):499-505. PMC: 4476499. DOI: 10.1038/nsmb.2991. View

14.

Choi D, Kwon K, Hwang D, Koo J, Um H, Song H . Treadmill Exercise Alleviates Brain Iron Dyshomeostasis Accelerating Neuronal Amyloid-β Production, Neuronal Cell Death, and Cognitive Impairment in Transgenic Mice Model of Alzheimer's Disease. Mol Neurobiol. 2021; 58(7):3208-3223. DOI: 10.1007/s12035-021-02335-8. View

15.

Latunde-Dada G, Simpson R, Mckie A . Recent advances in mammalian haem transport. Trends Biochem Sci. 2006; 31(3):182-8. DOI: 10.1016/j.tibs.2006.01.005. View

16.

Wan W, Cao L, Kalionis B, Murthi P, Xia S, Guan Y . Iron Deposition Leads to Hyperphosphorylation of Tau and Disruption of Insulin Signaling. Front Neurol. 2019; 10:607. PMC: 6593079. DOI: 10.3389/fneur.2019.00607. View

17.

Li C, Deng X, Xie X, Liu Y, Friedmann Angeli J, Lai L . Activation of Glutathione Peroxidase 4 as a Novel Anti-inflammatory Strategy. Front Pharmacol. 2018; 9:1120. PMC: 6178849. DOI: 10.3389/fphar.2018.01120. View

18.

Si Z, Wang X . The Neuroprotective and Neurodegeneration Effects of Heme Oxygenase-1 in Alzheimer's Disease. J Alzheimers Dis. 2020; 78(4):1259-1272. DOI: 10.3233/JAD-200720. View

19.

Gauthier S, Feldman H, Schneider L, Wilcock G, Frisoni G, Hardlund J . Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet. 2016; 388(10062):2873-2884. PMC: 5164296. DOI: 10.1016/S0140-6736(16)31275-2. View

20.

van Duijn S, Bulk M, van Duinen S, Nabuurs R, van Buchem M, van der Weerd L . Cortical Iron Reflects Severity of Alzheimer's Disease. J Alzheimers Dis. 2017; 60(4):1533-1545. PMC: 5676973. DOI: 10.3233/JAD-161143. View