Aerobic Exercise Regulates Apoptosis Through the PI3K/Akt/GSK-3 Signaling Pathway to Improve Cognitive Impairment in Alzheimer's Disease Mice

Overview

Journal Neural Plast

Specialty Neurology

Date 2022 Sep 20

PMID 36124291

Authors

Yan Peng

Rui Chi

Gang Liu

Weijie Tian

Jun Zhang

Rihui Zhang

Affiliations

Soon will be listed here.

Abstract

Neuronal apoptosis is an important factor in the etiology of Alzheimer's disease (AD). Aerobic exercise (AE) enhances learning and memory, improves cognitive impairment, increases telomere binding protein expression, and decreases apoptosis regulators, but it remains unclear whether it can improve cognitive impairment caused by neuronal apoptosis in AD. Therefore, this study investigated whether an 8-week running table exercise intervention could reduce apoptosis and improve cognitive function in the hippocampal neurons of AD model mice. After the exercise intervention, we evaluated the learning memory ability (positioning, navigation, and spatial search) of mice using a Morris water labyrinth, Nissl staining, immunohistochemistry, and protein application to detect hippocampal PI3K/Akt/GSK-3 signaling pathway protein and hippocampal neuronal cell apoptosis protein B cell lymphoma 2 (Bcl-2) and apoptosis-promoting protein bcl-2-related X (Bax) protein expression. The results showed that aerobic exercise improved the location and spatial exploration ability of mice, increased the number of PI3K- and p-Akt-positive cells, increased the expression of PI3K, p-Akt, and bcl-2 proteins, decreased the expression of GSK-3 and Bax proteins, and increased the bcl-2/Bax ratio of mice. The results suggest that aerobic exercise can reduce apoptosis and improve cognitive function in AD mice. The molecular mechanism may involve activation of the PI3K/Akt/GSK-3 signaling pathway.

Citing Articles

Interplay between PI3k/AKT signaling and caspase pathway in Alzheimer disease: mechanism and therapeutic implications.

Bhatia V, Vikram V, Chandel A, Rattan A Inflammopharmacology. 2025; .

PMID: 40088370 DOI: 10.1007/s10787-025-01715-z.

Oral Administration of and Ameliorates Amyloid Beta (Aβ)-Induced Cognitive Impairment by Improving Synaptic Function Through Regulation of TLR4/Akt Pathway.

Choi H, Lee H, Kim I, Ju Y, Heo Y, Na H Antioxidants (Basel). 2025; 14(2).

PMID: 40002326 PMC: 11851505. DOI: 10.3390/antiox14020139.

High-intensity interval training combined with cannabidiol supplementation improves cognitive impairment by regulating the expression of apolipoprotein E, presenilin-1, and glutamate proteins in a rat model of amyloid β-induced Alzheimer's disease.

Kordi M, Khademi N, Zobeydi A, Torabi S, Mahmoodifar E, Gaeini A Iran J Basic Med Sci. 2024; 27(12):1583-1591.

PMID: 39539449 PMC: 11556759. DOI: 10.22038/ijbms.2024.79464.17210.

Efficacy of exercise rehabilitation for managing patients with Alzheimer's disease.

Li D, Jia J, Zeng H, Zhong X, Chen H, Yi C Neural Regen Res. 2024; 19(10):2175-2188.

PMID: 38488551 PMC: 11034587. DOI: 10.4103/1673-5374.391308.

Aerobic exercise combined with chlorogenic acid exerts neuroprotective effects and reverses cognitive decline in Alzheimer's disease model mice (APP/PS1) via the SIRT1/ /PGC-1α/PPARγ signaling pathway.

Shi D, Hao Z, Qi W, Jiang F, Liu K, Shi X Front Aging Neurosci. 2023; 15:1269952.

PMID: 38046466 PMC: 10693339. DOI: 10.3389/fnagi.2023.1269952.

References

Kumar M, Bansal N . Implications of Phosphoinositide 3-Kinase-Akt (PI3K-Akt) Pathway in the Pathogenesis of Alzheimer's Disease. Mol Neurobiol. 2021; 59(1):354-385. DOI: 10.1007/s12035-021-02611-7. View

Johnson J, Mercado-Ayon E, Mercado-Ayon Y, Dong Y, Halawani S, Ngaba L . Mitochondrial dysfunction in the development and progression of neurodegenerative diseases. Arch Biochem Biophys. 2020; 702:108698. DOI: 10.1016/j.abb.2020.108698. View

He C, Huang Z, Yu C, Wang H, Zhou H, Kong L . Epigenetic Regulation of Amyloid-beta Metabolism in Alzheimer's Disease. Curr Med Sci. 2021; 40(6):1022-1030. DOI: 10.1007/s11596-020-2283-0. View

Erickson K, Prakash R, Voss M, Chaddock L, Hu L, Morris K . Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus. 2009; 19(10):1030-9. PMC: 3072565. DOI: 10.1002/hipo.20547. View

Jung S, Kim D, Yune T, Shin D, Baek S, Kim C . Treadmill exercise reduces spinal cord injury-induced apoptosis by activating the PI3K/Akt pathway in rats. Exp Ther Med. 2014; 7(3):587-593. PMC: 3919853. DOI: 10.3892/etm.2013.1451. View

Kvansakul M, Caria S, Hinds M . The Bcl-2 Family in Host-Virus Interactions. Viruses. 2017; 9(10). PMC: 5691641. DOI: 10.3390/v9100290. View

Andreotti D, Silva J, Matumoto A, Orellana A, de Mello P, Kawamoto E . Effects of Physical Exercise on Autophagy and Apoptosis in Aged Brain: Human and Animal Studies. Front Nutr. 2020; 7:94. PMC: 7399146. DOI: 10.3389/fnut.2020.00094. View

Isla A, Vazquez-Cuevas F, Pena-Ortega F . Exercise Prevents Amyloid-β-Induced Hippocampal Network Disruption by Inhibiting GSK3β Activation. J Alzheimers Dis. 2016; 52(1):333-43. DOI: 10.3233/JAD-150352. View

de Sousa Fernandes M, Ordonio T, Santos G, Santos L, Calazans C, Gomes D . Effects of Physical Exercise on Neuroplasticity and Brain Function: A Systematic Review in Human and Animal Studies. Neural Plast. 2021; 2020:8856621. PMC: 7752270. DOI: 10.1155/2020/8856621. View

10.

Liang J, Wang H, Zeng Y, Qu Y, Liu Q, Zhao F . Physical exercise promotes brain remodeling by regulating epigenetics, neuroplasticity and neurotrophins. Rev Neurosci. 2021; 32(6):615-629. DOI: 10.1515/revneuro-2020-0099. View

11.

Jahangiri Z, Gholamnezhad Z, Hosseini M . Neuroprotective effects of exercise in rodent models of memory deficit and Alzheimer's. Metab Brain Dis. 2018; 34(1):21-37. DOI: 10.1007/s11011-018-0343-y. View

12.

Garatachea N, Pareja-Galeano H, Sanchis-Gomar F, Santos-Lozano A, Fiuza-Luces C, Moran M . Exercise attenuates the major hallmarks of aging. Rejuvenation Res. 2014; 18(1):57-89. PMC: 4340807. DOI: 10.1089/rej.2014.1623. View

13.

Roberts A . Therapeutic development and current uses of BCL-2 inhibition. Hematology Am Soc Hematol Educ Program. 2020; 2020(1):1-9. PMC: 7727569. DOI: 10.1182/hematology.2020000154. View

14.

Liu S, Gao J, Zhu M, Liu K, Zhang H . Gut Microbiota and Dysbiosis in Alzheimer's Disease: Implications for Pathogenesis and Treatment. Mol Neurobiol. 2020; 57(12):5026-5043. PMC: 7541367. DOI: 10.1007/s12035-020-02073-3. View

15.

Zhao G, Liu H, Zhang H, Tong X . Treadmill exercise enhances synaptic plasticity, but does not alter β-amyloid deposition in hippocampi of aged APP/PS1 transgenic mice. Neuroscience. 2015; 298:357-66. DOI: 10.1016/j.neuroscience.2015.04.038. View

16.

de Freitas G, Lourenco M, De Felice F . Protective actions of exercise-related FNDC5/Irisin in memory and Alzheimer's disease. J Neurochem. 2020; 155(6):602-611. DOI: 10.1111/jnc.15039. View

17.

Martini F, Regis Leite M, Rosa S, Klann I, Nogueira C . Strength exercise suppresses STZ-induced spatial memory impairment and modulates BDNF/ERK-CAMKII/CREB signalling pathway in the hippocampus of mice. Cell Biochem Funct. 2020; 38(2):213-221. DOI: 10.1002/cbf.3470. View

18.

Yao Y, Wang Y, Kong L, Chen Y, Yang J . RETRACTED: Osthole decreases tau protein phosphorylation via PI3K/AKT/GSK-3β signaling pathway in Alzheimer's disease. Life Sci. 2018; 217:16-24. DOI: 10.1016/j.lfs.2018.11.038. View

19.

Wang H, Megill A, He K, Kirkwood A, Lee H . Consequences of inhibiting amyloid precursor protein processing enzymes on synaptic function and plasticity. Neural Plast. 2012; 2012:272374. PMC: 3390164. DOI: 10.1155/2012/272374. View

20.

Liang P, Li L, Zhang Y, Shen Y, Zhang L, Zhou J . Electroacupuncture Improves Clearance of Amyloid- through the Glymphatic System in the SAMP8 Mouse Model of Alzheimer's Disease. Neural Plast. 2021; 2021:9960304. PMC: 8416373. DOI: 10.1155/2021/9960304. View