Understanding the Molecular Impact of Physical Exercise on Alzheimer’s Disease
Abstract
1. Introduction
2. Alzheimer’s Disease
3. Role of Physical Exercise on Alzheimer’s Disease Patients
4. Alzheimer’s Disease and Physical Exercise Intervention: Molecular Mechanisms
4.1. Amyloid Precursor Protein and Amyloid β-Protein Pathology: Molecular Mechanisms
PE Intervention Effect on APP and Aβ Molecular Mechanisms
4.2. Tau Pathology and Neurofibrillary Tangle: Molecular Mechanisms
PE Effect on Tau Pathology Molecular Mechanisms
4.3. Neuroglia and Neuroinflammation in AD: Molecular Mechanisms
PE Effect on Neuroglia Molecular Mechanisms in AD
4.4. Mitochondrial Dysfunction in AD: Molecular Mechanisms
PE Effect on Mitochondrial Dysfunction Molecular Mechanisms in AD
4.5. Oxidative Stress on AD: Molecular Mechanisms
PE Effect on Oxidative Stress Molecular Mechanisms in AD
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Sheppard, O.; Coleman, M. Alzheimer’s Disease: Etiology, Neuropathology and Pathogenesis. In Alzheimer’s Disease: Drug Discovery; Huang, X., Ed.; Exon Publications: Brisbane, Australia, 2020; ISBN 978-0-6450017-0-9. [Google Scholar]
- Scheltens, P.; De Strooper, B.; Kivipelto, M.; Holstege, H.; Chételat, G.; Teunissen, C.E.; Cummings, J.; van der Flier, W.M. Alzheimer’s disease. Lancet 2021, 397, 1577–1590. [Google Scholar] [CrossRef] [PubMed]
- Gale, S.A.; Acar, D.; Daffner, K.R. Dementia. Am. J. Med. 2018, 131, 1161–1169. [Google Scholar] [CrossRef] [PubMed]
- Mazon, J.N.; de Mello, A.H.; Ferreira, G.K.; Rezin, G.T. The impact of obesity on neurodegenerative diseases. Life Sci. 2017, 182, 22–28. [Google Scholar] [CrossRef] [PubMed]
- Agnello, L.; Ciaccio, M. Neurodegenerative Diseases: From Molecular Basis to Therapy. Int. J. Mol. Sci. 2022, 23, 12854. [Google Scholar] [CrossRef]
- Collaborators, G.D.F. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019. Lancet Public Health 2022, 7, e105–e125. [Google Scholar] [CrossRef]
- Temple, S. Advancing cell therapy for neurodegenerative diseases. Cell Stem Cell 2023, 30, 512–529. [Google Scholar] [CrossRef]
- Batool, S.; Raza, H.; Zaidi, J.; Riaz, S.; Hasan, S.; Syed, N.I. Synapse formation: From cellular and molecular mechanisms to neurodevelopmental and neurodegenerative disorders. J. Neurophysiol. 2019, 121, 1381–1397. [Google Scholar] [CrossRef]
- Serrano, M.E.; Kim, E.; Petrinovic, M.M.; Turkheimer, F.; Cash, D. Imaging Synaptic Density: The Next Holy Grail of Neuroscience? Front. Neurosci. 2022, 16, 796129. [Google Scholar] [CrossRef]
- Hormuzdi, S.G.; Filippov, M.A.; Mitropoulou, G.; Monyer, H.; Bruzzone, R. Electrical synapses: A dynamic signaling system that shapes the activity of neuronal networks. Biochim. Biophys. Acta Biomembr. 2004, 1662, 113–137. [Google Scholar] [CrossRef]
- Shin, M.; Wang, Y.; Borgus, J.R.; Venton, B.J. Electrochemistry at the Synapse. Annu. Rev. Anal. Chem. 2019, 12, 297–321. [Google Scholar] [CrossRef]
- Tisher, A.; Salardini, A. A Comprehensive Update on Treatment of Dementia. Semin. Neurol. 2019, 39, 167–178. [Google Scholar] [CrossRef] [PubMed]
- Farì, G.; Lunetti, P.; Pignatelli, G.; Raele, M.V.; Cera, A.; Mintrone, G.; Ranieri, M.; Megna, M.; Capobianco, L. The Effect of Physical Exercise on Cognitive Impairment in Neurodegenerative Disease: From Pathophysiology to Clinical and Rehabilitative Aspects. Int. J. Mol. Sci. 2021, 22, 11632. [Google Scholar] [CrossRef] [PubMed]
- Mahalakshmi, B.; Maurya, N.; Lee, S.D.; Bharath Kumar, V. Possible Neuroprotective Mechanisms of Physical Exercise in Neurodegeneration. Int. J. Mol. Sci. 2020, 21, 5895. [Google Scholar] [CrossRef] [PubMed]
- Xu, X.; Fu, Z.; Le, W. Exercise and Parkinson’s disease. Int. Rev. Neurobiol. 2019, 147, 45–74. [Google Scholar] [CrossRef]
- Cui, M.Y.; Lin, Y.; Sheng, J.Y.; Zhang, X.; Cui, R.J. Exercise Intervention Associated with Cognitive Improvement in Alzheimer’s Disease. Neural Plast. 2018, 2018, 9234105. [Google Scholar] [CrossRef]
- Alzheimer’s disease facts and figures. Alzheimers Dement. 2023, 19, 1598–1695. [CrossRef]
- Twarowski, B.; Herbet, M. Inflammatory Processes in Alzheimer’s Disease-Pathomechanism, Diagnosis and Treatment: A Review. Int. J. Mol. Sci. 2023, 24, 6518. [Google Scholar] [CrossRef]
- Gustavsson, A.; Norton, N.; Fast, T.; Frölich, L.; Georges, J.; Holzapfel, D.; Kirabali, T.; Krolak-Salmon, P.; Rossini, P.M.; Ferretti, M.T.; et al. Global estimates on the number of persons across the Alzheimer’s disease continuum. Alzheimer’s Dement. 2023, 19, 658–670. [Google Scholar] [CrossRef]
- Qiu, C.; Kivipelto, M.; von Strauss, E. Epidemiology of Alzheimer’s disease: Occurrence, determinants, and strategies toward intervention. Dialogues Clin. Neurosci. 2009, 11, 111–128. [Google Scholar] [CrossRef]
- Aggarwal, N.T.; Mielke, M.M. Sex Differences in Alzheimer’s Disease. Neurol. Clin. 2023, 41, 343–358. [Google Scholar] [CrossRef]
- Breijyeh, Z.; Karaman, R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules 2020, 25, 5789. [Google Scholar] [CrossRef] [PubMed]
- Rostagno, A.A. Pathogenesis of Alzheimer’s Disease. Int. J. Mol. Sci. 2022, 24, 107. [Google Scholar] [CrossRef] [PubMed]
- Eratne, D.; Loi, S.M.; Farrand, S.; Kelso, W.; Velakoulis, D.; Looi, J.C. Alzheimer’s disease: Clinical update on epidemiology, pathophysiology and diagnosis. Australas. Psychiatry 2018, 26, 347–357. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.X.; Tian, Y.; Wang, Z.T.; Ma, Y.H.; Tan, L.; Yu, J.T. The Epidemiology of Alzheimer’s Disease Modifiable Risk Factors and Prevention. J. Prev. Alzheimer’s Dis. 2021, 8, 313–321. [Google Scholar] [CrossRef]
- Atri, A. The Alzheimer’s Disease Clinical Spectrum: Diagnosis and Management. Med. Clin. 2019, 103, 263–293. [Google Scholar] [CrossRef]
- Porsteinsson, A.P.; Isaacson, R.S.; Knox, S.; Sabbagh, M.N.; Rubino, I. Diagnosis of Early Alzheimer’s Disease: Clinical Practice in 2021. J. Prev. Alzheimer’s Dis. 2021, 8, 371–386. [Google Scholar] [CrossRef]
- Monteiro, A.R.; Barbosa, D.J.; Remião, F.; Silva, R. Alzheimer’s disease: Insights and new prospects in disease pathophysiology, biomarkers and disease-modifying drugs. Biochem. Pharmacol. 2023, 211, 115522. [Google Scholar] [CrossRef]
- Vermunt, L.; Sikkes, S.A.M.; van den Hout, A.; Handels, R.; Bos, I.; van der Flier, W.M.; Kern, S.; Ousset, P.J.; Maruff, P.; Skoog, I.; et al. Duration of preclinical, prodromal, and dementia stages of Alzheimer’s disease in relation to age, sex, and APOE genotype. Alzheimer’s Dement. 2019, 15, 888–898. [Google Scholar] [CrossRef]
- Hampel, H.; Hu, Y.; Cummings, J.; Mattke, S.; Iwatsubo, T.; Nakamura, A.; Vellas, B.; O’Bryant, S.; Shaw, L.M.; Cho, M.; et al. Blood-based biomarkers for Alzheimer’s disease: Current state and future use in a transformed global healthcare landscape. Neuron 2023, 111, 2781–2799. [Google Scholar] [CrossRef]
- Lane, C.A.; Hardy, J.; Schott, J.M. Alzheimer’s disease. Eur. J. Neurol. 2018, 25, 59–70. [Google Scholar] [CrossRef]
- Dubois, B.; Villain, N.; Frisoni, G.B.; Rabinovici, G.D.; Sabbagh, M.; Cappa, S.; Bejanin, A.; Bombois, S.; Epelbaum, S.; Teichmann, M.; et al. Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group. Lancet Neurol. 2021, 20, 484–496. [Google Scholar] [CrossRef] [PubMed]
- Cummings, J.L.; Dubois, B.; Molinuevo, J.L.; Scheltens, P. International Work Group criteria for the diagnosis of Alzheimer disease. Med. Clin. 2013, 97, 363–368. [Google Scholar] [CrossRef] [PubMed]
- McKhann, G.M.; Knopman, D.S.; Chertkow, H.; Hyman, B.T.; Jack, C.R.; Kawas, C.H.; Klunk, W.E.; Koroshetz, W.J.; Manly, J.J.; Mayeux, R.; et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s Dement. 2011, 7, 263–269. [Google Scholar] [CrossRef] [PubMed]
- Zhou, R.; Ji, B.; Kong, Y.; Qin, L.; Ren, W.; Guan, Y.; Ni, R. PET Imaging of Neuroinflammation in Alzheimer’s Disease. Front. Immunol. 2021, 12, 739130. [Google Scholar] [CrossRef]
- Altuna-Azkargorta, M.; Mendioroz-Iriarte, M. Blood biomarkers in Alzheimer’s disease. Neurologia 2021, 36, 704–710. [Google Scholar] [CrossRef]
- Reitz, C. Genetic diagnosis and prognosis of Alzheimer’s disease: Challenges and opportunities. Expert Rev. Mol. Diagn. 2015, 15, 339–348. [Google Scholar] [CrossRef]
- Khan, S.; Barve, K.H.; Kumar, M.S. Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease. Curr. Neuropharmacol. 2020, 18, 1106–1125. [Google Scholar] [CrossRef]
- Kim, B.; Noh, G.O.; Kim, K. Behavioural and psychological symptoms of dementia in patients with Alzheimer’s disease and family caregiver burden: A path analysis. BMC Geriatr. 2021, 21, 160. [Google Scholar] [CrossRef]
- Chu, L.W. Alzheimer’s disease: Early diagnosis and treatment. Hong Kong Med. J. 2012, 18, 228–237. [Google Scholar]
- Pîrşcoveanu, D.F.V.; Pirici, I.; Tudorică, V.; Bălşeanu, T.A.; Albu, V.C.; Bondari, S.; Bumbea, A.M.; Pîrşcoveanu, M. Tau protein in neurodegenerative diseases—A review. Rom. J. Morphol. Embryol. 2017, 58, 1141–1150. [Google Scholar]
- Fakhoury, M. Inflammation in Alzheimer’s Disease. Curr. Alzheimer Res. 2020, 17, 959–961. [Google Scholar] [CrossRef] [PubMed]
- Jia, R.X.; Liang, J.H.; Xu, Y.; Wang, Y.Q. Effects of physical activity and exercise on the cognitive function of patients with Alzheimer disease: A meta-analysis. BMC Geriatr. 2019, 19, 181. [Google Scholar] [CrossRef] [PubMed]
- Deslandes, A.; Moraes, H.; Ferreira, C.; Veiga, H.; Silveira, H.; Mouta, R.; Pompeu, F.A.; Coutinho, E.S.; Laks, J. Exercise and mental health: Many reasons to move. Neuropsychobiology 2009, 59, 191–198. [Google Scholar] [CrossRef] [PubMed]
- Valenzuela, P.L.; Castillo-García, A.; Morales, J.S.; de la Villa, P.; Hampel, H.; Emanuele, E.; Lista, S.; Lucia, A. Exercise benefits on Alzheimer’s disease: State-of-the-science. Ageing Res. Rev. 2020, 62, 101108. [Google Scholar] [CrossRef]
- Memon, A.A.; Coleman, J.J.; Amara, A.W. Effects of exercise on sleep in neurodegenerative disease. Neurobiol. Dis. 2020, 140, 104859. [Google Scholar] [CrossRef]
- Cámara-Calmaestra, R.; Martínez-Amat, A.; Aibar-Almazán, A.; Hita-Contreras, F.; de Miguel Hernando, N.; Achalandabaso-Ochoa, A. Effectiveness of Physical Exercise on Alzheimer’s disease. A Systematic Review. J. Prev. Alzheimer’s Dis. 2022, 9, 601–616. [Google Scholar] [CrossRef]
- De la Rosa, A.; Olaso-Gonzalez, G.; Arc-Chagnaud, C.; Millan, F.; Salvador-Pascual, A.; García-Lucerga, C.; Blasco-Lafarga, C.; Garcia-Dominguez, E.; Carretero, A.; Correas, A.G.; et al. Physical exercise in the prevention and treatment of Alzheimer’s disease. J. Sport Health Sci. 2020, 9, 394–404. [Google Scholar] [CrossRef]
- Dawson, N.; Judge, K.S.; Gerhart, H. Improved Functional Performance in Individuals With Dementia After a Moderate-Intensity Home-Based Exercise Program: A Randomized Controlled Trial. J. Geriatr. Phys. Ther. 2019, 42, 18–27. [Google Scholar] [CrossRef]
- López-Ortiz, S.; Valenzuela, P.L.; Seisdedos, M.M.; Morales, J.S.; Vega, T.; Castillo-García, A.; Nisticò, R.; Mercuri, N.B.; Lista, S.; Lucia, A.; et al. Exercise interventions in Alzheimer’s disease: A systematic review and meta-analysis of randomized controlled trials. Ageing Res. Rev. 2021, 72, 101479. [Google Scholar] [CrossRef]
- López-Ortiz, S.; Lista, S.; Valenzuela, P.L.; Pinto-Fraga, J.; Carmona, R.; Caraci, F.; Caruso, G.; Toschi, N.; Emanuele, E.; Gabelle, A.; et al. Effects of physical activity and exercise interventions on Alzheimer’s disease: An umbrella review of existing meta-analyses. J. Neurol. 2023, 270, 711–725. [Google Scholar] [CrossRef]
- Stephen, R.; Hongisto, K.; Solomon, A.; Lönnroos, E. Physical Activity and Alzheimer’s Disease: A Systematic Review. J. Gerontol. Ser. A Biomed. Sci. Med. Sci. 2017, 72, 733–739. [Google Scholar] [CrossRef] [PubMed]
- Coelho, F.G.; Vital, T.M.; Stein, A.M.; Arantes, F.J.; Rueda, A.V.; Camarini, R.; Teodorov, E.; Santos-Galduróz, R.F. Acute aerobic exercise increases brain-derived neurotrophic factor levels in elderly with Alzheimer’s disease. J. Alzheimer’s Dis. 2014, 39, 401–408. [Google Scholar] [CrossRef] [PubMed]
- Vecchio, L.M.; Meng, Y.; Xhima, K.; Lipsman, N.; Hamani, C.; Aubert, I. The Neuroprotective Effects of Exercise: Maintaining a Healthy Brain Throughout Aging. Brain Plast. 2018, 4, 17–52. [Google Scholar] [CrossRef] [PubMed]
- Powers, S.K.; Deminice, R.; Ozdemir, M.; Yoshihara, T.; Bomkamp, M.P.; Hyatt, H. Exercise-induced oxidative stress: Friend or foe? J. Sport Health Sci. 2020, 9, 415–425. [Google Scholar] [CrossRef]
- Ye, M.; Dewi, L.; Liao, Y.C.; Nicholls, A.; Huang, C.Y.; Kuo, C.H. DNA oxidation after exercise: A systematic review and meta-analysis. Front. Physiol. 2023, 14, 1275867. [Google Scholar] [CrossRef]
- Leong, Y.Q.; Ng, K.Y.; Chye, S.M.; Ling, A.P.K.; Koh, R.Y. Mechanisms of action of amyloid-beta and its precursor protein in neuronal cell death. Metab. Brain Dis. 2020, 35, 11–30. [Google Scholar] [CrossRef]
- Hur, J.Y. γ-Secretase in Alzheimer’s disease. Exp. Mol. Med. 2022, 54, 433–446. [Google Scholar] [CrossRef]
- Tan, J.Z.A.; Gleeson, P.A. The role of membrane trafficking in the processing of amyloid precursor protein and production of amyloid peptides in Alzheimer’s disease. Biochim. Biophys. Acta Biomembr. 2019, 1861, 697–712. [Google Scholar] [CrossRef]
- O’Brien, R.J.; Wong, P.C. Amyloid precursor protein processing and Alzheimer’s disease. Annu. Rev. Neurosci. 2011, 34, 185–204. [Google Scholar] [CrossRef]
- Cho, Y.; Bae, H.G.; Okun, E.; Arumugam, T.V.; Jo, D.G. Physiology and pharmacology of amyloid precursor protein. Pharmacol. Ther. 2022, 235, 108122. [Google Scholar] [CrossRef]
- Strope, T.A.; Wilkins, H.M. The reciprocal relationship between amyloid precursor protein and mitochondrial function. J. Neurochem. 2024, 168, 2275–2284. [Google Scholar] [CrossRef] [PubMed]
- Sehar, U.; Rawat, P.; Reddy, A.P.; Kopel, J.; Reddy, P.H. Amyloid Beta in Aging and Alzheimer’s Disease. Int. J. Mol. Sci. 2022, 23, 12924. [Google Scholar] [CrossRef] [PubMed]
- Chen, J.; Chen, J.S.; Li, S.; Zhang, F.; Deng, J.; Zeng, L.H.; Tan, J. Amyloid Precursor Protein: A Regulatory Hub in Alzheimer’s Disease. Aging Dis. 2024, 15, 201–225. [Google Scholar] [CrossRef] [PubMed]
- Orobets, K.S.; Karamyshev, A.L. Amyloid Precursor Protein and Alzheimer’s Disease. Int. J. Mol. Sci. 2023, 24, 14794. [Google Scholar] [CrossRef] [PubMed]
- Chau, D.D.; Ng, L.L.; Zhai, Y.; Lau, K.F. Amyloid precursor protein and its interacting proteins in neurodevelopment. Biochem. Soc. Trans. 2023, 51, 1647–1659. [Google Scholar] [CrossRef]
- Chen, M.; Wang, J.; Jiang, J.; Zheng, X.; Justice, N.J.; Wang, K.; Ran, X.; Li, Y.; Huo, Q.; Zhang, J.; et al. APP modulates KCC2 expression and function in hippocampal GABAergic inhibition. Elife 2017, 6, e20142. [Google Scholar] [CrossRef]
- Hua, K.Y.; Zhao, W.J. Current study on diagnosis and treatment of Alzheimer’s disease by targeting amyloid b-protein. Folia Neuropathol. 2023, 61, 8–15. [Google Scholar] [CrossRef]
- Meleleo, D.; Notarachille, G.; Mangini, V.; Arnesano, F. Concentration-dependent effects of mercury and lead on Aβ42: Possible implications for Alzheimer’s disease. Eur. Biophys. J. 2019, 48, 173–187. [Google Scholar] [CrossRef]
- Yadollahikhales, G.; Rojas, J.C. Anti-Amyloid Immunotherapies for Alzheimer’s Disease: A 2023 Clinical Update. Neurotherapeutics 2023, 20, 914–931. [Google Scholar] [CrossRef]
- Baracaldo-Santamaría, D.; Avendaño-Lopez, S.S.; Ariza-Salamanca, D.F.; Rodriguez-Giraldo, M.; Calderon-Ospina, C.A.; González-Reyes, R.E.; Nava-Mesa, M.O. Role of Calcium Modulation in the Pathophysiology and Treatment of Alzheimer’s Disease. Int. J. Mol. Sci. 2023, 24, 9067. [Google Scholar] [CrossRef]
- Carapeto, A.P.; Marcuello, C.; Faísca, P.F.N.; Rodrigues, M.S. Morphological and Biophysical Study of S100A9 Protein Fibrils by Atomic Force Microscopy Imaging and Nanomechanical Analysis. Biomolecules 2024, 14, 1091. [Google Scholar] [CrossRef] [PubMed]
- Ziaunys, M.; Sakalauskas, A.; Mikalauskaite, K.; Smirnovas, V. Polymorphism of Alpha-Synuclein Amyloid Fibrils Depends on Ionic Strength and Protein Concentration. Int. J. Mol. Sci. 2021, 22, 12382. [Google Scholar] [CrossRef] [PubMed]
- Delport, A.; Hewer, R. The amyloid precursor protein: A converging point in Alzheimer’s disease. Mol. Neurobiol. 2022, 59, 4501–4516. [Google Scholar] [CrossRef] [PubMed]
- Liu, H.L.; Zhao, G.; Zhang, H.; Shi, L.D. Long-term treadmill exercise inhibits the progression of Alzheimer’s disease-like neuropathology in the hippocampus of APP/PS1 transgenic mice. Behav. Brain Res. 2013, 256, 261–272. [Google Scholar] [CrossRef]
- Liu, Y.; Chu, J.M.T.; Yan, T.; Zhang, Y.; Chen, Y.; Chang, R.C.C.; Wong, G.T.C. Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer’s disease mice. J. Neuroinflamm. 2020, 17, 4. [Google Scholar] [CrossRef]
- Wu, C.; Yang, L.; Tucker, D.; Dong, Y.; Zhu, L.; Duan, R.; Liu, T.C.; Zhang, Q. Beneficial Effects of Exercise Pretreatment in a Sporadic Alzheimer’s Rat Model. Med. Sci. Sports Exerc. 2018, 50, 945–956. [Google Scholar] [CrossRef]
- Khodadadi, D.; Gharakhanlou, R.; Naghdi, N.; Salimi, M.; Azimi, M.; Shahed, A.; Heysieattalab, S. Treadmill Exercise Ameliorates Spatial Learning and Memory Deficits Through Improving the Clearance of Peripheral and Central Amyloid-Beta Levels. Neurochem. Res. 2018, 43, 1561–1574. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- Hashiguchi, D.; Campos, H.C.; Wuo-Silva, R.; Faber, J.; Gomes da Silva, S.; Coppi, A.A.; Arida, R.M.; Longo, B.M. Resistance Exercise Decreases Amyloid Load and Modulates Inflammatory Responses in the APP/PS1 Mouse Model for Alzheimer’s Disease. J. Alzheimer’s Dis. 2020, 73, 1525–1539. [Google Scholar] [CrossRef]
- Yang, L.; Wu, C.; Li, Y.; Dong, Y.; Wu, C.Y.; Lee, R.H.; Brann, D.W.; Lin, H.W.; Zhang, Q. Long-term exercise pre-training attenuates Alzheimer’s disease-related pathology in a transgenic rat model of Alzheimer’s disease. Geroscience 2022, 44, 1457–1477. [Google Scholar] [CrossRef]
- Zhao, N.; Zhang, X.; Li, B.; Wang, J.; Zhang, C.; Xu, B. Treadmill Exercise Improves PINK1/Parkin-Mediated Mitophagy Activity Against Alzheimer’s Disease Pathologies by Upregulated SIRT1-FOXO1/3 Axis in APP/PS1 Mice. Mol. Neurobiol. 2023, 60, 277–291. [Google Scholar] [CrossRef] [PubMed]
- Lu, Y.; Dong, Y.; Tucker, D.; Wang, R.; Ahmed, M.E.; Brann, D.; Zhang, Q. Treadmill Exercise Exerts Neuroprotection and Regulates Microglial Polarization and Oxidative Stress in a Streptozotocin-Induced Rat Model of Sporadic Alzheimer’s Disease. J. Alzheimer’s Dis. 2017, 56, 1469–1484. [Google Scholar] [CrossRef] [PubMed]
- Li, B.; Liang, F.; Ding, X.; Yan, Q.; Zhao, Y.; Zhang, X.; Bai, Y.; Huang, T.; Xu, B. Interval and continuous exercise overcome memory deficits related to β-Amyloid accumulation through modulating mitochondrial dynamics. Behav. Brain Res. 2019, 376, 112171. [Google Scholar] [CrossRef]
- Zhang, X.; He, Q.; Huang, T.; Zhao, N.; Liang, F.; Xu, B.; Chen, X.; Li, T.; Bi, J. Treadmill Exercise Decreases Aβ Deposition and Counteracts Cognitive Decline in APP/PS1 Mice, Possibly. Front. Aging Neurosci. 2019, 11, 78. [Google Scholar] [CrossRef] [PubMed]
- Svensson, M.; Andersson, E.; Manouchehrian, O.; Yang, Y.; Deierborg, T. Voluntary running does not reduce neuroinflammation or improve non-cognitive behavior in the 5xFAD mouse model of Alzheimer’s disease. Sci. Rep. 2020, 10, 1346. [Google Scholar] [CrossRef]
- Ornish, D.; Madison, C.; Kivipelto, M.; Kemp, C.; McCulloch, C.E.; Galasko, D.; Artz, J.; Rentz, D.; Lin, J.; Norman, K.; et al. Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer’s disease: A randomized, controlled clinical trial. Alzheimer’s Res. Ther. 2024, 16, 122. [Google Scholar] [CrossRef]
- Sewell, K.R.; Rainey-Smith, S.R.; Pedrini, S.; Peiffer, J.J.; Sohrabi, H.R.; Taddei, K.; Markovic, S.J.; Martins, R.N.; Brown, B.M. The impact of exercise on blood-based biomarkers of Alzheimer’s disease in cognitively unimpaired older adults. Geroscience 2024, 46, 5911–5923. [Google Scholar] [CrossRef]
- Steen Jensen, C.; Portelius, E.; Siersma, V.; Høgh, P.; Wermuth, L.; Blennow, K.; Zetterberg, H.; Waldemar, G.; Gregers Hasselbalch, S.; Hviid Simonsen, A. Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Moderate- to High-Intensity Physical Exercise in Patients with Alzheimer Disease. Dement. Geriatr. Cogn. Disord. 2016, 42, 146–158. [Google Scholar] [CrossRef]
- Vidoni, E.D.; Morris, J.K.; Watts, A.; Perry, M.; Clutton, J.; Van Sciver, A.; Kamat, A.S.; Mahnken, J.; Hunt, S.L.; Townley, R.; et al. Effect of aerobic exercise on amyloid accumulation in preclinical Alzheimer’s: A 1-year randomized controlled trial. PLoS ONE 2021, 16, e0244893. [Google Scholar] [CrossRef]
- Singh, A.; Ansari, V.A.; Mahmood, T.; Hasan, S.M.; Wasim, R.; Maheshwari, S.; Akhtar, J.; Sheikh, S.; Vishwakarma, V.K. Targeting Abnormal Tau Phosphorylation for Alzheimer’s Therapeutics. Horm. Metab. Res. 2024, 56, 482–488. [Google Scholar] [CrossRef]
- Wu, X.L.; Piña-Crespo, J.; Zhang, Y.W.; Chen, X.C.; Xu, H.X. Tau-mediated Neurodegeneration and Potential Implications in Diagnosis and Treatment of Alzheimer’s Disease. Chin. Med. J. 2017, 130, 2978–2990. [Google Scholar] [CrossRef] [PubMed]
- Naseri, N.N.; Wang, H.; Guo, J.; Sharma, M.; Luo, W. The complexity of tau in Alzheimer’s disease. Neurosci. Lett. 2019, 705, 183–194. [Google Scholar] [CrossRef] [PubMed]
- Sayas, C.L.; Ávila, J. GSK-3 and Tau: A Key Duet in Alzheimer’s Disease. Cells 2021, 10, 721. [Google Scholar] [CrossRef] [PubMed]
- Bitra, V.R.; Challa, S.R.; Adiukwu, P.C.; Rapaka, D. Tau trajectory in Alzheimer’s disease: Evidence from the connectome-based computational models. Brain Res. Bull. 2023, 203, 110777. [Google Scholar] [CrossRef]
- Sinsky, J.; Pichlerova, K.; Hanes, J. Tau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies. Int. J. Mol. Sci. 2021, 22, 9207. [Google Scholar] [CrossRef]
- Guo, T.; Zhang, D.; Zeng, Y.; Huang, T.Y.; Xu, H.; Zhao, Y. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Mol. Neurodegener. 2020, 15, 40. [Google Scholar] [CrossRef]
- Hamano, T.; Enomoto, S.; Shirafuji, N.; Ikawa, M.; Yamamura, O.; Yen, S.H.; Nakamoto, Y. Autophagy and Tau Protein. Int. J. Mol. Sci. 2021, 22, 7475. [Google Scholar] [CrossRef]
- Zhang, H.; Wei, W.; Zhao, M.; Ma, L.; Jiang, X.; Pei, H.; Cao, Y.; Li, H. Interaction between Aβ and Tau in the Pathogenesis of Alzheimer’s Disease. Int. J. Biol. Sci. 2021, 17, 2181–2192. [Google Scholar] [CrossRef]
- Salas, I.H.; Burgado, J.; Allen, N.J. Glia: Victims or villains of the aging brain? Neurobiol. Dis. 2020, 143, 105008. [Google Scholar] [CrossRef]
- Wang, C.; Zong, S.; Cui, X.; Wang, X.; Wu, S.; Wang, L.; Liu, Y.; Lu, Z. The effects of microglia-associated neuroinflammation on Alzheimer’s disease. Front. Immunol. 2023, 14, 1117172. [Google Scholar] [CrossRef]
- Fujikawa, R.; Tsuda, M. The Functions and Phenotypes of Microglia in Alzheimer’s Disease. Cells 2023, 12, 1207. [Google Scholar] [CrossRef] [PubMed]
- Merighi, S.; Nigro, M.; Travagli, A.; Gessi, S. Microglia and Alzheimer’s Disease. Int. J. Mol. Sci. 2022, 23, 12990. [Google Scholar] [CrossRef] [PubMed]
- Wu, Y.; Eisel, U.L.M. Microglia-Astrocyte Communication in Alzheimer’s Disease. J. Alzheimer’s Dis. 2023, 95, 785–803. [Google Scholar] [CrossRef] [PubMed]
- Sarlus, H.; Heneka, M.T. Microglia in Alzheimer’s disease. J. Clin. Investig. 2017, 127, 3240–3249. [Google Scholar] [CrossRef]
- Sun, E.; Motolani, A.; Campos, L.; Lu, T. The Pivotal Role of NF-kB in the Pathogenesis and Therapeutics of Alzheimer’s Disease. Int. J. Mol. Sci. 2022, 23, 8972. [Google Scholar] [CrossRef]
- Hashioka, S.; Wu, Z.; Klegeris, A. Glia-Driven Neuroinflammation and Systemic Inflammation in Alzheimer’s Disease. Curr. Neuropharmacol. 2021, 19, 908–924. [Google Scholar] [CrossRef]
- Stanca, S.; Rossetti, M.; Bongioanni, P. Astrocytes as Neuroimmunocytes in Alzheimer’s Disease: A Biochemical Tool in the Neuron-Glia Crosstalk along the Pathogenetic Pathways. Int. J. Mol. Sci. 2023, 24, 13880. [Google Scholar] [CrossRef]
- Abd El-Kader, S.M.; Al-Jiffri, O.H. Aerobic exercise improves quality of life, psychological well-being and systemic inflammation in subjects with Alzheimer’s disease. Afr. Health Sci. 2016, 16, 1045–1055. [Google Scholar] [CrossRef]
- Jensen, C.S.; Bahl, J.M.; Østergaard, L.B.; Høgh, P.; Wermuth, L.; Heslegrave, A.; Zetterberg, H.; Heegaard, N.H.H.; Hasselbalch, S.G.; Simonsen, A.H. Exercise as a potential modulator of inflammation in patients with Alzheimer’s disease measured in cerebrospinal fluid and plasma. Exp. Gerontol. 2019, 121, 91–98. [Google Scholar] [CrossRef]
- de Farias, J.M.; Dos Santos Tramontin, N.; Pereira, E.V.; de Moraes, G.L.; Furtado, B.G.; Tietbohl, L.T.W.; Da Costa Pereira, B.; Simon, K.U.; Muller, A.P. Physical Exercise Training Improves Judgment and Problem-Solving and Modulates Serum Biomarkers in Patients with Alzheimer’s Disease. Mol. Neurobiol. 2021, 58, 4217–4225. [Google Scholar] [CrossRef]
- Delgado-Peraza, F.; Nogueras-Ortiz, C.; Simonsen, A.H.; Knight, D.D.; Yao, P.J.; Goetzl, E.J.; Jensen, C.S.; Høgh, P.; Gottrup, H.; Vestergaard, K.; et al. Neuron-derived extracellular vesicles in blood reveal effects of exercise in Alzheimer’s disease. Alzheimer’s Res. Ther. 2023, 15, 156. [Google Scholar] [CrossRef] [PubMed]
- Jensen, C.S.; Portelius, E.; Høgh, P.; Wermuth, L.; Blennow, K.; Zetterberg, H.; Hasselbalch, S.G.; Simonsen, A.H. Effect of physical exercise on markers of neuronal dysfunction in cerebrospinal fluid in patients with Alzheimer’s disease. Alzheimer’s Dement. 2017, 3, 284–290. [Google Scholar] [CrossRef] [PubMed]
- Mary, A.; Eysert, F.; Checler, F.; Chami, M. Mitophagy in Alzheimer’s disease: Molecular defects and therapeutic approaches. Mol. Psychiatry 2023, 28, 202–216. [Google Scholar] [CrossRef] [PubMed]
- Maruthiyodan, S.; Mumbrekar, K.D.; Guruprasad, K.P. Involvement of mitochondria in Alzheimer’s disease pathogenesis and their potential as targets for phytotherapeutics. Mitochondrion 2024, 76, 101868. [Google Scholar] [CrossRef]
- Rivera, J.; Gangwani, L.; Kumar, S. Mitochondria Localized microRNAs: An Unexplored miRNA Niche in Alzheimer’s Disease and Aging. Cells 2023, 12, 742. [Google Scholar] [CrossRef]
- Li, Y.; Xia, X.; Wang, Y.; Zheng, J.C. Mitochondrial dysfunction in microglia: A novel perspective for pathogenesis of Alzheimer’s disease. J. Neuroinflamm. 2022, 19, 248. [Google Scholar] [CrossRef]
- Flannery, P.J.; Trushina, E. Mitochondrial dynamics and transport in Alzheimer’s disease. Mol. Cell Neurosci. 2019, 98, 109–120. [Google Scholar] [CrossRef]
- Wang, W.; Zhao, F.; Ma, X.; Perry, G.; Zhu, X. Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances. Mol. Neurodegener. 2020, 15, 30. [Google Scholar] [CrossRef]
- Kerr, J.S.; Adriaanse, B.A.; Greig, N.H.; Mattson, M.P.; Cader, M.Z.; Bohr, V.A.; Fang, E.F. Mitophagy and Alzheimer’s Disease: Cellular and Molecular Mechanisms. Trends Neurosci. 2017, 40, 151–166. [Google Scholar] [CrossRef]
- Gowda, P.; Reddy, P.H.; Kumar, S. Deregulated mitochondrial microRNAs in Alzheimer’s disease: Focus on synapse and mitochondria. Ageing Res. Rev. 2022, 73, 101529. [Google Scholar] [CrossRef]
- Roy, R.G.; Mandal, P.K.; Maroon, J.C. Oxidative Stress Occurs Prior to Amyloid Aβ Plaque Formation and Tau Phosphorylation in Alzheimer’s Disease: Role of Glutathione and Metal Ions. ACS Chem. Neurosci. 2023, 14, 2944–2954. [Google Scholar] [CrossRef] [PubMed]
- Rummel, N.G.; Butterfield, D.A. Altered Metabolism in Alzheimer Disease Brain: Role of Oxidative Stress. Antioxid. Redox Signal. 2022, 36, 1289–1305. [Google Scholar] [CrossRef] [PubMed]
- Veselov, I.M.; Vinogradova, D.V.; Maltsev, A.V.; Shevtsov, P.N.; Spirkova, E.A.; Bachurin, S.O.; Shevtsova, E.F. Mitochondria and Oxidative Stress as a Link between Alzheimer’s Disease and Diabetes Mellitus. Int. J. Mol. Sci. 2023, 24, 14450. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Wang, W.; Li, L.; Perry, G.; Lee, H.G.; Zhu, X. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim. Biophys. Acta Mol. Basis Dis. 2014, 1842, 1240–1247. [Google Scholar] [CrossRef]
- Cheignon, C.; Tomas, M.; Bonnefont-Rousselot, D.; Faller, P.; Hureau, C.; Collin, F. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol. 2018, 14, 450–464. [Google Scholar] [CrossRef]
Reference | Study Population | Intervention | Results |
---|---|---|---|
Liu et al. [75] | Three-month-old mice:
| Treadmill exercise:
| TgE vs. TgC:
|
Lu et al. [83] | Sprague Dawley rats:
| Treadmill exercise:
| STZe vs. STZc:
|
Wu et al. [77] | Sprague Dawley rats:
| Swimming exercise:
| STZe vs. STZc:
|
Khodadadi et al. [78] | Eight-month-old Wistar rats:
| Treadmill exercise:
| Aβe vs. Aβc:
|
Zhang et al. [85] | Three-month-old mice:
| Treadmill exercise:
| TgE vs. TgC:
|
Xia et al. [79] | Three-month-old mice:
| Treadmill exercise:
| TgE vs. TgC:
|
Hashiguchi et al. [80] | Six- to seven-month-old mice:
| Resistance exercise:
| TgE vs. TgC:
|
Svensson et al. [86] | Nine- to twelve-week-old mice:
| Voluntary exercise:
| TgE vs. TgC:
|
Liu et al. [76] | Nine-month-old mice:
| Resistance exercise:
| TgE vs. TgC:
|
Yang et al. [81] | Two-month-old rats:
| Treadmill exercise:
| TgE vs. TgC:
|
Zhao et al. [82] | Three-month-old mice:
| Treadmill exercise:
| TgE vs. TgC:
|
Li et al. [84] | Three-month-old mice:
| HIIT protocol:
| TgHIIT and TgMICT vs. TgC:
|
Reference | Study Population | Intervention | Results |
---|---|---|---|
Sewell et al. [88] | Cognitively impaired adults
| Cycling on an ergometer:
| Plasma AD-related biomarkers pre- vs. post-intervention:
|
Ornish et al. [87] | MCI AD patients
| Intensive multimodal lifestyle intervention:
| Intervention group vs. control group:
|
Delgado-Peraza et al. [112] | Mild to moderate AD patients:
| Aerobic training:
| Exercise group vs. control group:
|
de Farias et al. [111] | Female AD patients (n = 15) | Functional training:
| Blood AD-related biomarkers pre- vs. post-intervention:
|
Vidoni et al. [90] | Preclinical AD adults (elevated levels of cerebral amyloid)
| Aerobic exercise:
| Exercise group vs. control group: There were no differences in change measures of amyloid or brain volume. |
Jensen et al. [110] | Mild AD patients
| Aerobic exercise:
| Exercise group vs. control group:
|
Jensen et al. [113] | Mild AD patients
| Aerobic exercise:
| Exercise group vs. control group:
|
Abd El-Kader and Al-Jiffri [109] | AD patients
| Treadmill aerobic exercise:
| Exercise group vs. control group:
|
Steen Jensen et al. [89] | Mild AD patients
| Aerobic exercise:
| Exercise group vs. control group:
|
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Cantón-Suárez, A.; Sánchez-Valdeón, L.; Bello-Corral, L.; Cuevas, M.J.; Estébanez, B. Understanding the Molecular Impact of Physical Exercise on Alzheimer’s Disease. Int. J. Mol. Sci. 2024, 25, 13576. https://doi.org/10.3390/ijms252413576
Cantón-Suárez A, Sánchez-Valdeón L, Bello-Corral L, Cuevas MJ, Estébanez B. Understanding the Molecular Impact of Physical Exercise on Alzheimer’s Disease. International Journal of Molecular Sciences. 2024; 25(24):13576. https://doi.org/10.3390/ijms252413576
Chicago/Turabian StyleCantón-Suárez, Alba, Leticia Sánchez-Valdeón, Laura Bello-Corral, María J. Cuevas, and Brisamar Estébanez. 2024. "Understanding the Molecular Impact of Physical Exercise on Alzheimer’s Disease" International Journal of Molecular Sciences 25, no. 24: 13576. https://doi.org/10.3390/ijms252413576
APA StyleCantón-Suárez, A., Sánchez-Valdeón, L., Bello-Corral, L., Cuevas, M. J., & Estébanez, B. (2024). Understanding the Molecular Impact of Physical Exercise on Alzheimer’s Disease. International Journal of Molecular Sciences, 25(24), 13576. https://doi.org/10.3390/ijms252413576