Long-term exercise training inhibits inflammation by suppressing hippocampal NLRP3 in APP/PS1 mice

Abstract

Behavioral experiments have demonstrated that long-term physical exercise can be beneficial for learning and memory dysfunction caused by neuroinflammation in Alzheimer's disease (AD). However, the molecular mechanism remains poorly understood due to a lack of sufficient pertinent biochemical evidence. We investigated the potential effect of long-term physical exercise on cognition and hippocampal gene and protein expression changes in a transgenic AD mouse model. Following twenty weeks of treadmill exercise, transgenic AD mice showed improvement in cognitive functions and downregulation of Nod-like receptor protein 3 (NLRP3) (p ​< ​0.01), interleukin-1beta (IL-1β) (p ​< ​0.05), and amyloid-β_1-42 (Aβ_1-42) (p ​< ​0.05) expression levels. In addition, we observed significant reductions of microglial activation and hippocampal neuronal damage in the exercised AD mice (p ​< ​0.01), which might be a result of the downregulation of NLRP3-mediated signaling and neuro-inflammatory responses. As neuronal damage due to inflammation might be a likely cause of AD-associated cognitive dysfunction. Our results suggested that the anti-inflammatory effects of exercise training involved downregulating the expression of key inflammatory factors and might play an important role in protecting hippocampal neurons against damage during the course of AD.

Keywords

Exercise / NLRP3 / Neuroinflammation / Hippocampus / APP/PS1 mice / Alzheimer's

Authors’ contributions

Xue Li: Writing - Review & Editing, Conceptualization; Yu Jin: Writing - Original Draft, Visualization; Xianyi Ding: Data Curation; Tongyang Zhu: Completion of the experiment; Changling Wei: Modification; Li Yao: Methodology.

Funding

This work is supported by the Sports Medicine Key Laboratory of Sichuan Province/Sports Medicine Key Laboratory of State Sport General Administration (Grant No. 2023-A015), the Innovative Project of Sports Medicine and Health Institute/Zheng Huaixian Bone and Trauma Research Institute (Grant No. CX21A02), the "14th Five Year Plan" Scientific Research and Innovation Team of Chengdu Sport University (Grant No. 23CXTD02).

Submission statement

All authors have read and agree with manuscript content. The manuscript is only communicated to the Journal, the manuscript will not be submitted elsewhere for review and publication.

Ethical approval statement for animal use

All experimental protocols about animals were approved by the Laboratory Animal Ethics Committee at Chengdu Sports University and were performed in accordance with the National Guidance for Animal Experiments (approval number 202113).

Conflict of interest

The authors declare that they have no competing financial interests or personal relationships related to this work.

Acknowledge Statement

The authors have no acknowledgments to report.

References

[1] C.L. Masters, R. Bateman, K. Blennow, C.C. Rowe, R.A. Sperling, J.L. Cummings. Alzheimer's disease. Nat Rev Dis Prim, 1 ( 2015), Article 15056, DOI: 10.1038/nrdp.2015.56

[2] M. Baumgart, H.M. Snyder, M.C. Carrillo, S. Fazio, H. Kim, H. Johns. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective. Alzheimers Dement, 11 (6) ( 2015), pp. 718-726, DOI: 10.1016/j.jalz.2015.05.016

[3] V. Calsolaro, P. Edison. Neuroinflammation in Alzheimer's disease: current evidence and future directions. Alzheimers Dement, 12 (6) ( 2016), pp. 719-732, DOI: 10.1016/j.jalz.2016.02.010

[4] W.C. Pierre, P.L.P. Smith, I. Londono, S. Chemtob, C. Mallard, G.A. Lodygensky. Neonatal microglia: the cornerstone of brain fate. Brain Behav Immun, 59 ( 2017), pp. 333-345, DOI: 10.1016/j.bbi.2016.08.018

[5] H. Sarlus, M.T. Heneka. Microglia in Alzheimer's disease. J Clin Invest, 127 (9) ( 2017), pp. 3240-3249, DOI: 10.1172/JCI90606

[6] M.M. Wang, D. Miao, X.P. Cao, L. Tan, L. Tan.Innate immune activation in Alzheimer's disease. Ann Transl Med, 6 (10) ( 2018), p. 177, DOI: 10.21037/atm.2018.04.20

[7] T. Ngandu, J. Lehtisalo, A. Solomon, et al.. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet, 385 (9984) ( 2015), pp. 2255-2263, DOI: 10.1016/S0140-6736(15)60461-5

[8] P. Scheltens, K. Blennow, M.M. Breteler, et al.. Alzheimer's disease. Lancet, 388 (10043) ( 2016), pp. 505-517, DOI: 10.1016/S0140-6736(15)01124-1

[9] G.M. Petzinger, B.E. Fisher, S. McEwen, J.A. Beeler, J.P. Walsh, M.W. Jakowec. Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson's disease. Lancet Neurol, 12 (7) ( 2013), pp. 716-726, DOI: 10.1016/S1474-4422(13)70123-6

[10] M.V. Lourenco, R.L. Frozza, G.B. de Freitas, et al.. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Nat Med, 25 (1) ( 2019), pp. 165-175, DOI: 10.1038/s41591-018-0275-4

[11] A.M. Horowitz, X. Fan, G. Bieri, et al.. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science, 369 (6500) ( 2020), pp. 167-173, DOI: 10.1126/science.aaw2622

[12] P.L. Valenzuela, A. Castillo-García, J.S. Morales, et al.. Exercise benefits on Alzheimer's disease: State-of-the-science. Ageing Res Rev, 62 ( 2020), Article 101108, DOI: 10.1016/j.arr.2020.101108

[13] X. Li, L. Wang, S. Zhang, X. Hu, H. Yang, L. Xi.Timing-dependent protection of swimming exercise against d-galactose-induced aging-like impairments in spatial learning/memory in rats. Brain Sci, 9 (9) ( 2019), p. 236, DOI: 10.3390/brainsci9090236

[14] D.D.L. Scheffer, A. Latini. Exercise-induced immune system response: anti-inflammatory status on peripheral and central organs. Biochim Biophys Acta, Mol Basis Dis, 1866 (10) ( 2020), Article 165823, DOI: 10.1016/j.bbadis.2020.165823

[15] M.T. Heneka, M.P. Kummer, A. Stutz, et al.. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature, 493 (7434) ( 2013), pp. 674-678, DOI: 10.1038/nature11729

[16] A. Halle, V. Hornung, G.C. Petzold, et al.. The NALP 3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol, 9 (8) ( 2008), pp. 857-865, DOI: 10.1038/ni.1636

[17] Y.S. Feng, Z.X. Tan, L.Y. Wu, F. Dong, F. Zhang.The involvement of NLRP3 inflammasome in the treatment of Alzheimer's disease. Ageing Res Rev, 64 ( 2020), Article 101192, DOI: 10.1016/j.arr.2020.101192

[18] M. Haneklaus, L.A. O'Neill. NLRP 3 at the interface of metabolism and inflammation. Immunol Rev, 265 (1) ( 2015), pp. 53-62, DOI: 10.1111/imr.12285

[19] E.J. Baker, T.T. Gleeson. The effects of intensity on the energetics of brief locomotor activity. J Exp Biol, 202 (Pt 22) ( 1999), pp. 3081-3087, DOI: 10.1242/jeb.202.22.3081

[20] C.V. Vorhees, M.T. Williams. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc, 1 (2) ( 2006), pp. 848-858, DOI: 10.1038/nprot.2006.116

[21] J. Mei, J. Kohler, Y. Winter, et al.. Automated radial 8-arm maze: a voluntary and stress-free behavior test to assess spatial learning and memory in mice. Behav Brain Res, 381 ( 2020), Article 112352, DOI: 10.1016/j.bbr.2019.112352

[22] E. Baerends, K. Soud, J. Folke, et al.. Modeling the early stages of Alzheimer's disease by administering intracerebroventricular injections of human native Aβ oligomers to rats. Acta Neuropathol Commun, 10 (1) ( 2022), p. 113, DOI: 10.1186/s40478-022-01417-5

[23] P. Faucher, N. Mons, J. Micheau, C. Louis, D.J. Beracochea.Hippocampal injections of oligomeric amyloid β-peptide (1-42) induce selective working memory deficits and long-lasting alterations of ERK signaling pathway. Front Aging Neurosci, 7 ( 2016), p. 245, DOI: 10.3389/fnagi.2015.00245

[24] B. Calvo-Flores Guzmán, T. Elizabeth Chaffey, T. Hansika Palpagama, et al.. The interplay between beta-amyloid 1-42 ( Aβ1-42)-Induced hippocampal inflammatory response, p-tau, vascular pathology, and their synergistic contributions to neuronal death and behavioral deficits. Front Mol Neurosci, 13 ( 2020), Article 522073, DOI: 10.3389/fnmol.2020.552073

[25] H.Y. Kim, D.K. Lee, B.R. Chung, H.V. Kim, Y. Kim. Intracerebroventricular injection of amyloid-β peptides in normal mice to acutely induce alzheimer-like cognitive deficits. J Vis Exp, 109 ( 2016), Article 53308, DOI: 10.3791/53308

[26] M. Prinz, J. Priller, S.S. Sisodia, R.M. Ransohoff. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci, 14 (10) ( 2011), pp. 1227-1235, DOI: 10.1038/nn.2923

[27] M.T. Heneka, D.T. Golenbock, E. Latz. Innate immunity in Alzheimer's disease. Nat Immunol, 16 (3) ( 2015), pp. 229-236, DOI: 10.1038/ni.3102

[28] Q. Meng, M.S. Lin, I.S. Tzeng.Relationship between exercise and Alzheimer's disease: a narrative literature review. Front Neurosci, 14 ( 2020), p. 131, DOI: 10.3389/fnins.2020.00131

[29] W.W. Chen, X. Zhang, W.J. Huang. Role of physical exercise in Alzheimer's disease. Biomed Rep, 4 (4) ( 2016), pp. 403-407, DOI: 10.3892/br.2016.607

[30] S.H. Yang, D.K. Lee, J. Shin, et al.. Nec-1 alleviates cognitive impairment with reduction of Aβ and tau abnormalities in APP/PS1 mice. EMBO Mol Med, 9 (1) ( 2017), pp. 61-77, DOI: 10.15252/emmm.201606566

[31] M.S. Finch, A. Bagit, D.M. Marko. Amyloid beta 42 oligomers induce neuronal and synaptic receptor dysfunctions. J Physiol, 598 (17) ( 2020), pp. 3545-3546, DOI: 10.1113/JP280038

[32] P.N. Nirmalraj, J. List, S. Battacharya, et al.. Complete aggregation pathway of amyloid β (1-40) and (1-42) resolved on an atomically clean interface. Sci Adv, 6 (15) ( 2020), Article eaaz6014, DOI: 10.1126/sciadv.aaz6014

[33] M. Saresella, F. La Rosa, F. Piancone, et al.. The NLRP3 and NLRP 1 inflammasomes are activated in Alzheimer's disease. Mol Neurodegener, 11 ( 2016), p. 23, DOI: 10.1186/s13024-016-0088-1

[34] Y. Xu, H. Sheng, Q. Bao, Y. Wang, J. Lu, X. Ni. NLRP 3 inflammasome activation mediates estrogen deficiency-induced depression- and anxiety-like behavior and hippocampal inflammation in mice. Brain Behav Immun, 56 ( 2016), pp. 175-186, DOI: 10.1016/j.bbi.2016.02.022

[35] A.M. Birch, L. Katsouri, M. Sastre.Modulation of inflammation in transgenic models of Alzheimer's disease. J Neuroinflammation, 11 ( 2014), p. 25, DOI: 10.1186/1742-2094-11-25

[36] Z. De Miguel, N. Khoury, M.J. Betley, et al.. Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature, 600 (7889) ( 2021), pp. 494-499, DOI: 10.1038/s41586-021-04183-x

[37] L. Sominsky, S. De Luca, S.J. Spencer. Microglia: key players in neurodevelopment and neuronal plasticity. Int J Biochem Cell Biol, 94 ( 2018), pp. 56-60, DOI: 10.1016/j.biocel.2017.11.012