Effect of Complex Voluntary Wheel Running on Hippocampal histology and Necroptosis Related Genes Expression level and Spatial Memory Function in Rat Model of Alzheimer's Disease

Zeini Zadeh, Kosar; Zarneshan, Azam; Azali Alamdari, Karim

doi:10.22059/jsb.2023.362788.1597

Document Type : Research Paper I Open Access I Released under CC BY-NC 4.0 license

Authors

¹ Department of sports Sciences, Faculty of Education and Psychology, Azarbaijan Shahid Madani University, Tabriz, Iran.

² Department of Sport Physiology, Faculty of Education and Psychology, Azerbaijan Shahid Madani University, Tabriz, Iran

³ Corresponding Author, Department of Sport Sciences, Faculty of Education and Psychology, Azarbaijan Shahid Madani University, Tabriz, Iran.

https://doi.org/10.22059/jsb.2023.362788.1597

Abstract

Introduction: Effect of complex voluntary wheel running on necroptosis and inflammation related hippocampal genes’ expression level and spatial memory function in rat model of Alzheimer's disease (AD) is not fully elucidated. Methods: 60 male Wistar rats (age: 4-6 weeks) were randomized into three groups of control-healthy (H-C), control-Alzheimer (C-ALZ), and complex wheel running-Alzheimer (CWheel-ALZ). AD induction was verified using shuttle box test two weeks following brain ventricle STZ injection and CWheel-ALZ animals experienced 12 weeks of complex voluntary wheel running in the following. Hippocampal CA1 pyramidal cell layer thickness and neuronal density (histochemical analysis) and necroptosis related hippocampal genes’ expression level were measured by PCER method following euthanasia. Data were compared using ANOVA with Tukey's post hoc test. Results: CA1 cell layer thickness and neuronal density were lower, while duration of spatial memory task, time to exhaustion and expression level of necroptosis related genes were higher in C-ALZ compared to H-C (P<0.05). In spite of restoration of all of variables in CWheel-ALZ animals (significant differences was observed compared to C-ALZ group), remarkable differences with H-C were still present after intervention (P<0.05). Conclusion: AD elevates likelihood of hippocampal inflammation and necroptosis along with both physical and mental performances. Complex wheel running fails to fully assuage the adverse effects from AD, in spite of some appreciable amendments could be provided. However; more research still warranted to be because of study limitations and lack of similar evidence done in this area.

Keywords

Main Subjects

Exercise Physiology

References

[1] Liu-Seifert H, Siemers E, Sundell K, Price K, Han B, Selzler K, et al. Cognitive and functional decline and their relationship in patients with mild Alzheimer's dementia. Journal of Alzheimer's Disease. 2015;43(3):949-55. DOI: 10.3233/JAD-140792

[2] Zahodne LB, Manly JJ, MacKay-Brandt A, Stern Y. Cognitive declines precede and predict functional declines in aging and Alzheimer’s disease. PloS one. 2013;8(9):e73645. doi.org/10.1371/journal.pone.0073645

[3] Dickerson B, Stoub T, Shah R, Sperling R, Killiany R, Albert M, et al. Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults. Neurology. 2011;76(16):1395-402. doi.org/10.1212/WNL.0b013e3182166e96

[4] Popescu BO, Ankarcrona M. Mechanisms of cell death in Alzheimer's disease: role of presenilins. Journal of Alzheimer's disease. 2004;6(2):123-8. DOI: 10.3233/JAD-2004-6203

[5] Zhu X, Raina AK, Perry G, Smith MA. Apoptosis in Alzheimer disease: a mathematical improbability. Current Alzheimer Research. 2006;3(4):393-6. doi.org/10.2174/156720506778249470

[6] Niikura T, Tajima H, Kita Y. Neuronal cell death in Alzheimer's disease and a neuroprotective factor, humanin. Current neuropharmacology. 2006;4(2):139-47. doi.org/10.2174/157015906776359577

[7] Lalaoui N, Lindqvist LM, Sandow JJ, Ekert PG, editors. The molecular relationships between apoptosis, autophagy and necroptosis. Seminars in cell & developmental biology; 2015: Elsevier. doi.org/10.1016/j.semcdb.2015.02.003

[8] He S. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009;137. doi.org/10.1016/j.cell.2009.05.021

[9] Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature chemical biology. 2005;1(2):112-9. doi.org/10.1038/nchembio711

[10] Newton K, Manning G. Necroptosis and inflammation. Annual review of biochemistry. 2016;85:743-63. DOI: 10.1146/annurev-biochem-060815-014830

[11] Zhao W, Liu Y, Xu L, He Y, Cai Z, Yu J, et al. Targeting Necroptosis as a Promising Therapy for Alzheimer’s Disease. 2022. DIO: 10.1021/acschemneuro.2c00172

[12] Hanson B. Necroptosis: A new way of dying? Cancer biology & therapy. 2016;17(9):899-910.

[13] Linkermann A, Green DR. Necroptosis. New England Journal of Medicine. 2014;370(5):455-65.

[14] Dondelinger Y, Declercq W, Montessuit S, Roelandt R, Goncalves A, Bruggeman I, et al. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell reports. 2014;7(4):971-81.

[15]Wang H, Sun L, Su L, Rizo J, Liu L, Wang L-F, et al. Mixed Lineage Kinase Domain-like Protein MLKL Causes Necrotic Membrane Disruption upon Phosphorylation by RIP3. Molecular Cell. 2014;54(1):133-46.

[16]Zheng C, Zhou X-W, Wang J-Z. The dual roles of cytokines in Alzheimer’s disease: update on interleukins, TNF-α, TGF-β and IFN-γ. Translational neurodegeneration. 2016;5(1):1-15.

[17] Jayaraman A, Htike TT, James R, Picon C, Reynolds R. TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus. Acta neuropathologica communications. 2021;9(1):1-21.

[18] Yu Z, Jiang N, Su W, Zhuo YJFiP. Necroptosis: a novel pathway in neuroinflammation. 2021;12.

[19] Yang SH, Lee DK, Shin J, Lee S, Baek S, Kim J, et al. Nec‐1 alleviates cognitive impairment with reduction of Aβ and tau abnormalities in APP/PS1 mice. 2017;9(1):61.

[20] Caccamo A, Branca C, Piras IS, Ferreira E, Huentelman MJ, Liang WS, et al. Necroptosis activation in Alzheimer's disease. 2017;20(9):1236-46.

[21] López-Ortiz S, Pinto-Fraga J, Valenzuela PL, Martín-Hernández J, Seisdedos MM, García-López O, et al. Physical exercise and Alzheimer’s disease: effects on pathophysiological molecular pathways of the disease. 2021;22(6):2897.

[22] Sujkowski AL, Hong L, Wessells R, Todi SVJARR. The protective role of exercise against age-related neurodegeneration. 2021:101543.

[23] Fuller OK, Whitham M, Mathivanan S, Febbraio MA. The protective effect of exercise in neurodegenerative diseases: the potential role of extracellular vesicles. Cells. 2020;9(10):2182.

[24] Ghardashi Afousi A, Gaeini A, Rakhshan K, Naderi N, Darbandi Azar A, Aboutaleb N. Targeting necroptotic cell death pathway by high-intensity interval training (HIIT) decreases development of post-ischemic adverse remodelling after myocardial ischemia / reperfusion injury. Journal of cell communication and signaling. 2019;13(2):255-67.

[25] Jahani M, Matin Homaie H, Farzanegi P. Effect of Continuous and Interval Exercise on the Necroptosis and Apoptosis of Endoplasmic Reticulum Proteins in the Heart of Diabetic Wistar Rats. Ilam-University-of-Medical-Sciences. 2020;28(5):53-63.

[26] Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014;505(7483):344-52.

[27] Gronek P, Balko S, Gronek J, Zajac A, Maszczyk A, Celka R, et al. Physical activity and Alzheimer’s disease: a narrative review. 2019;10(6):1282.

[28] Azevedo CV, Hashiguchi D, Campos HC, Figueiredo EV, Otaviano SFS, Penitente AR, et al. The effects of resistance exercise on cognitive function, amyloidogenesis, and neuroinflammation in Alzheimer’s disease. 2023;17:1131214.

[29] Huuha AM, Norevik CS, Moreira JBN, Kobro-Flatmoen A, Scrimgeour N, Kivipelto M, et al. Can exercise training teach us how to treat Alzheimer’s disease? Ageing Research Reviews. 2022;75:101559.

[30] Meng Q, Lin MS, Tzeng IS. Relationship Between Exercise and Alzheimer's Disease: A Narrative Literature Review. Frontiers in neuroscience. 2020;14:131.

[31] Mohammadikia E, Mohebbi F, Babaei HJJoSP, Conditioning A. The effect of 12 weeks aerobic training on TNF-α levels in the hippocampus and prefrontal cortex, and depression in rats with Alzheimer's disease.4(4):48.

[32] Liu Y, Chu JMT, Yan T, Zhang Y, Chen Y, Chang RCC, et al. Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer’s disease mice. 2020;17(1):1-16.

[33] Yanagita S, Amemiya S, Suzuki S, Kita IJLs. Effects of spontaneous and forced running on activation of hypothalamic corticotropin-releasing hormone neurons in rats. 2007;80(4):356-63.

[34] Belviranlı M, Okudan N. Voluntary, involuntary and forced exercises almost equally reverse behavioral impairment by regulating hippocampal neurotrophic factors and oxidative stress in experimental Alzheimer’s disease model. Behavioural Brain Research. 2019;364:245-55.

[35] Chomiak T, Block EW, Brown AR, Teskey GC, Hu B. Development and testing of a new system for assessing wheel-running behaviour in rodents. BMC Research Notes. 2016;9(1):262.

[36] McKenzie IA, Ohayon D, Li H, Paes de Faria J, Emery B, Tohyama K, et al. Motor skill learning requires active central myelination. science. 2014;346(6207):318-22.

[37] Fazelzadeh M, Afzalpour ME, Fallah Mohammadi Z, Falah Mohammadi H. The effects of voluntary complex and regular wheel running exercises on the levels of 8‐oxoguanine DNA glycosylase, semaphorin 3B, H2O2, and apoptosis in the hippocampus of diabetic rats. Brain and Behavior. 2021;11(3):e01988.

[38] Ferrer-Pérez C, Reguilón MD, Miñarro J, Rodríguez-Arias MJB. Effect of Voluntary Wheel-Running Exercise on the Endocrine and Inflammatory Response to Social Stress: Conditioned Rewarding Effects of Cocaine. 2022;10(10):2373.

[39] Manzanares G, Brito-da-Silva G, Gandra PJBJoM, Research B. Voluntary wheel running: patterns and physiological effects in mice. 2018;52.

[40] Yuede CM, Zimmerman SD, Dong H, Kling MJ, Bero AW, Holtzman DM, et al. Effects of voluntary and forced exercise on plaque deposition, hippocampal volume, and behavior in the Tg2576 mouse model of Alzheimer's disease. Neurobiology of Disease. 2009;35(3):426-32.

[41] Francis N, Robison LS, Popescu DL, Michaelos M, Hatfield J, Xu F, et al. Voluntary Wheel Running Reduces Amyloid-β 42 and Rescues Behavior in Aged Tg2576 Mouse Model of Alzheimer’s Disease. 2020;73(1):359-74.

[42] Adlard PA, Perreau VM, Pop V, Cotman CWJJoN. Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease. 2005;25(17):4217-21.

[43] Tapia‐Rojas C, Aranguiz F, Varela‐Nallar L, Inestrosa NCJBP. Voluntary Running Attenuates Memory Loss, Decreases Neuropathological Changes and Induces Neurogenesis in a Mouse Model of A lzheimer's Disease. 2016;26(1):62-74.

[44] Stewart S, Cacucci F, Lever CJJoAsd. Which memory task for my mouse? A systematic review of spatial memory performance in the Tg2576 Alzheimer's mouse model. 2011;26(1):105-26.

[45] Wolf SA, Kronenberg G, Lehmann K, Blankenship A, Overall R, Staufenbiel M, et al. Cognitive and Physical Activity Differently Modulate Disease Progression in the Amyloid Precursor Protein (APP)-23 Model of Alzheimer’s Disease. Biological Psychiatry. 2006;60(12):1314-23.

[46] Svensson M, Andersson E, Manouchehrian O, Yang Y, Deierborg TJSr. Voluntary running does not reduce neuroinflammation or improve non-cognitive behavior in the 5xFAD mouse model of Alzheimer’s disease. 2020;10(1):1-10.

[47] Richard R, Mousa S. Necroptosis in Alzheimer’s disease: Potential therapeutic target. Biomedicine & Pharmacotherapy. 2022;152:113203.

[48] Ahmadi f, fallahmohammadi z. THE EFFECT OF FOUR WEEKS' VOLUNTARY EXERCISE ON A REGULAR AND COMPLEX WHEEL RUNNING ON NG2 BRAIN LEVELS IN HEALTHY MALE WISTAR RATS %J Studies in Medical Sciences. 2019;29(12):896-903.

[49] McKenzie IA, Ohayon D, Li H, De Faria JP, Emery B, Tohyama K, et al. Motor skill learning requires active central myelination. science. 2014;346(6207):318-22.

[50] Soheili Kashani M, Salami M, Rezaei-Tavirani M, Talaei Zavareh SAJKJ. Maze training improves learning in an Alzheimer model of rat. 2010;14(3):209-16.

[51] Qin F, Dong Y, Wang S, Xu M, Wang Z, Qu C, et al. Maximum oxygen consumption and quantification of exercise intensity in untrained male Wistar rats. Scientific Reports. 2020;10(1):1-8.

[52] Mehta K, Kaur B, Pandey KK, Kaler S, Dhar P. Curcumin supplementation shows modulatory influence on functional and morphological features of hippocampus in mice subjected to arsenic trioxide exposure. Anatomy & Cell Biology. 2020;53(3):355-65.

[53] Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. methods. 2001;25(4):402-8.

[54] Thadathil N, Nicklas EH, Mohammed S, Lewis TL, Richardson A, Deepa SS. Necroptosis increases with age in the brain and contributes to age-related neuroinflammation. GeroScience. 2021;43(5):2345-61.

[55] Samson AL. MLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis. Nat Commun. 2020;11.

[56] Hosseini-Gerami L, Higgins IA, Collier DA, Laing E, Evans D, Broughton H, et al. Benchmarking causal reasoning algorithms for gene expression-based compound mechanism of action analysis. BMC Bioinformatics. 2023;24(1):154.

[57] Brod SA. Anti-Inflammatory Agents: An Approach to Prevent Cognitive Decline in Alzheimer's Disease. Journal of Alzheimer's disease : JAD. 2022;85(2):457-72.

[58] Stephenson J, Nutma E, van der Valk P, Amor SJI. Inflammation in CNS neurodegenerative diseases. 2018;154(2):204-19.

[59] Anna Catharina van L, Wiesje Maria van der F, Alle Meije W, Ellen D, Colin G, Jos T, et al. Cognitive reserve and clinical progression in Alzheimer disease. Neurology. 2019;93(4):e334.

[60] Van Loenhoud AC, van der Flier WM, Wink AM, Dicks E, Groot C, Twisk J, et al. Cognitive reserve and clinical progression in Alzheimer disease: a paradoxical relationship. 2019;93(4):e334-e46.

[61] Poddar J, Singh S, Kumar P, Bali S, Gupta S, Chakrabarti S. Inhibition of complex I-III activity of brain mitochondria after intracerebroventricular administration of streptozotocin in rats is possibly related to loss of body weight. Heliyon. 2020;6(7):e04490.

[62] Chen Y, Tian Z, Liang Z, Sun S, Dai C-l, Lee MH, et al. Brain Gene Expression of a Sporadic (icv-STZ Mouse) and a Familial Mouse Model (3xTg-AD Mouse) of Alzheimer’s Disease. PLOS ONE. 2012;7(12):e51432.

[63] Correia SC, Santos RX, Santos MS, Casadesus G, Lamanna JC, Perry G, et al. Mitochondrial abnormalities in a streptozotocin-induced rat model of sporadic Alzheimer's disease. Current Alzheimer research. 2013;10(4):406-19.

[64] Santos TdO, Mazucanti CHY, Xavier GF, Torrão AdS. Early and late neurodegeneration and memory disruption after intracerebroventricular streptozotocin. Physiology & Behavior. 2012;107(3):401-13.

[65] Zhou S, Yu G, Chi L, Zhu J, Zhang W, Zhang Y, et al. Neuroprotective effects of edaravone on cognitive deficit, oxidative stress and tau hyperphosphorylation induced by intracerebroventricular streptozotocin in rats. Neurotoxicology. 2013;38:136-45.

[66] Gutierres JM, Carvalho FB, Schetinger MR, Marisco P, Agostinho P, Rodrigues M, et al. Anthocyanins restore behavioral and biochemical changes caused by streptozotocin-induced sporadic dementia of Alzheimer's type. Life Sci. 2014;96(1-2):7-17.

[67] Du LL, Chai DM, Zhao LN, Li XH, Zhang FC, Zhang HB, et al. AMPK activation ameliorates Alzheimer's disease-like pathology and spatial memory impairment in a streptozotocin-induced Alzheimer's disease model in rats. Journal of Alzheimer's disease : JAD. 2015;43(3):775-84.

[68] Tang BLJT. Neuropathological mechanisms associated with pesticides in Alzheimer’s disease. 2020;8(2):21.

[69] Yan D, Zhang Y, Liu L, Yan HJSr. Pesticide exposure and risk of Alzheimer’s disease: A systematic review and meta-analysis. 2016;6(1):32222.

[70] Tu Y, Yang Y, Wang Y, Wu N, Tao J, Yang G, et al. Developmental exposure to chlorpyrifos causes neuroinflammation via necroptosis in mouse hippocampus and human microglial cell line. 2022;314:120217.

[71] Godbolt A, Waldman A, MacManus D, Schott J, Frost C, Cipolotti L, et al. MRS shows abnormalities before symptoms in familial Alzheimer disease. 2006;66(5):718-22.

[72] McDade E, Wang G, Gordon BA, Hassenstab J, Benzinger TL, Buckles V, et al. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. 2018;91(14):e1295-e306.

[73] Kamat PK. Streptozotocin induced Alzheimer's disease like changes and the underlying neural degeneration and regeneration mechanism. Neural regeneration research. 2015;10(7):1050-2.

[74] Roy A, Sharma S, Nag TC, Katyal J, Gupta YK, Jain S. Cognitive Dysfunction and Anxiety Resulting from Synaptic Downscaling, Hippocampal Atrophy, and Ventricular Enlargement with Intracerebroventricular Streptozotocin Injection in Male Wistar Rats. Neurotox Res. 2022;40(6):2179-202.

[75] Nasseri B, Zareian P, Alizade H. Apelin attenuates streptozotocin-induced learning and memory impairment by modulating necroptosis signaling pathway. International Immunopharmacology. 2020;84:106546.

[76] Silva SSL, Tureck LV, Souza LC, Mello-Hortega JV, Piumbini AL, Teixeira MD, et al. Animal model of Alzheimer’s disease induced by streptozotocin: New insights about cholinergic pathway. Brain research. 2023;1799:148175.

[77] Costa M, Bernardi J, Fiuza T, Costa L, Brandão R, Pereira ME. N-acetylcysteine protects memory decline induced by streptozotocin in mice. Chemico-biological interactions. 2016;253:10-7.

[78] Schwab BL, Guerini D, Didszun C, Bano D, Ferrando-May E, Fava E, et al. Cleavage of plasma membrane calcium pumps by caspases: a link between apoptosis and necrosis. Cell Death & Differentiation. 2002;9(8):818-31.

[79] Chen WN, Yeong KY. Scopolamine, a Toxin-Induced Experimental Model, Used for Research in Alzheimer's Disease. CNS & neurological disorders drug targets. 2020;19(2):85-93.

[80] Pluta R, Januszewski S, Czuczwar SJJFiAN. Brain ischemia as a prelude to Alzheimer's disease. 2021;13:636653.

[81] Pluta R, Miziak B, Czuczwar SJJIJoMS. Post-Ischemic Permeability of the Blood–Brain Barrier to Amyloid and Platelets as a Factor in the Maturation of Alzheimer’s Disease-Type Brain Neurodegeneration. 2023;24(13):10739.

[82] Stefanova N, Kozhevnikova O, Vitovtov A, Maksimova K, Logvinov S, Rudnitskaya E, et al. Senescence-accelerated OXYS rats: a model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease. 2014;13(6):898-909.

[83] Disterhoft JF, Moyer Jr JR, Thompson LTJAotNYAoS. The Calcium Rationale in Aging and Alzheimer's Disease: Evidence from an Animal Model of Normal Aging a. 1994;747(1):382-406.

[84] Richter H, Ambrée O, Lewejohann L, Herring A, Keyvani K, Paulus W, et al. Wheel-running in a transgenic mouse model of Alzheimer's disease: protection or symptom? 2008;190(1):74-84.

[85] Wang G, Zhou H-H, Luo L, Qin L-Q, Yin J, Yu Z, et al. Voluntary wheel running is capable of improving cognitive function only in the young but not the middle-aged male APPSwe/PS1De9 mice. 2021;145:105010.

[86] Salkovic-Petrisic M, Osmanovic J, Grünblatt E, Riederer P, Hoyer SJJoAsdJ. Modeling sporadic Alzheimer's disease: the insulin resistant brain state generates multiple long-term morphobiological abnormalities including hyperphosphorylated tau protein and amyloid-beta. 2009;18(4):729-50.

[87] Salkovic-Petrisic M, Osmanovic-Barilar J, Brückner MK, Hoyer S, Arendt T, Riederer PJJont. Cerebral amyloid angiopathy in streptozotocin rat model of sporadic Alzheimer’s disease: a long-term follow up study. 2011;118:765-72.

[88] Hampstead BM, Stringer AY, Iordan AD, Ploutz-Snyder R, Sathian K. Toward rational use of cognitive training in those with mild cognitive impairment. 2023;19(3):933-45.

[89] Bamidis PD, Fissler P, Papageorgiou SG, Zilidou V, Konstantinidis EI, Billis AS, et al. Gains in cognition through combined cognitive and physical training: the role of training dosage and severity of neurocognitive disorder. 2015;7:152.

[90] Belleville S, Cloutier S, Mellah S, Willis S, Vellas B, Andrieu S, et al. Is more always better? Dose effect in a multidomain intervention in older adults at risk of dementia. 2022;18(11):2140-50.

[91] Gallardo-Gómez D, del Pozo-Cruz J, Noetel M, Álvarez-Barbosa F, Alfonso-Rosa RM, del Pozo Cruz B. Optimal dose and type of exercise to improve cognitive function in older adults: A systematic review and bayesian model-based network meta-analysis of RCTs. Ageing Research Reviews. 2022;76:101591.

[92] Turner V, Husain MJAP, Translational,, Integration C. Anhedonia in neurodegenerative diseases. 2022:255-77.

[93] Natta LE, Melrose RJ, Harwood DG, Sultzer DLJTAJoGP. An examination of anhedonia separate from depression in Alzheimer's disease: a preliminary study. 2013;21(3):S78-S9.

[94] Scheggi S, De Montis MG, Gambarana CJIJoN. Making sense of rodent models of anhedonia. 2018;21(11):1049-65.

[95] Joubert C, Chainay HJCiia. Aging brain: the effect of combined cognitive and physical training on cognition as compared to cognitive and physical training alone–a systematic review. 2018:1267-301.

[96] Dare LR, Garcia A, Soares CB, Lopes L, Neves B-HS, Dias DV, et al. The reversal of memory deficits in an Alzheimer’s disease model using physical and cognitive exercise. 2020;14:152.

[97] Huang Y-Q, Wu C, He X-F, Wu D, He X, Liang F-Y, et al. Effects of voluntary wheel-running types on hippocampal neurogenesis and spatial cognition in middle-aged mice. Frontiers in Cellular Neuroscience. 2018;12:177.

[98] Lenizky M. The Effect of Working Memory on Corticospinal Excitability: University of Waterloo; 2020.

[99] Ehrenreich H, Garcia-Agudo LF, Steixner-Kumar AA, Wilke JB, Butt UJ. Introducing the brain erythropoietin circle to explain adaptive brain hardware upgrade and improved performance. Molecular Psychiatry. 2022;27(5):2372-9.

[100] Jin Y, Sun LH, Yang W, Cui RJ, Xu SB. The Role of BDNF in the Neuroimmune Axis Regulation of Mood Disorders. Frontiers in neurology. 2019;10:515.

[101] Liu Y, Liu F, Grundke‐Iqbal I, Iqbal K, Gong CXJTJop. Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes. 2011;225(1):54-62.

[102] Sergi G, De Rui M, Coin A, Inelmen EM, Manzato EJPotNS. Weight loss and Alzheimer's disease: temporal and aetiologic connections. 2013;72(1):160-5.

[103] Drzezga A, Lautenschlager N, Siebner H, Riemenschneider M, Willoch F, Minoshima S, et al. Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer's disease: a PET follow-up study. 2003;30:1104-13.

[104] Vyazovskiy VV, Fisher SP, Gemignani J, Summerer L, Vyazovskiy VV, Summerer L. Assessment of Physical Exercise Benefits on Brain Health for Long-Duration Spaceflight. 2017.

[105] Fisher SP, Cui N, McKillop LE, Gemignani J, Bannerman DM, Oliver PL, et al. Stereotypic wheel running decreases cortical activity in mice. 2016;7(1):13138.

[106] Nagai H, de Vivo L, Bellesi M, Ghilardi MF, Tononi G, Cirelli CJS. Sleep consolidates motor learning of complex movement sequences in mice. 2017;40(2):zsw059.

[107] Wisse L, Ravikumar S, Ittyerah R, Lim S, Lane J, Bedard M, et al. Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions. acta neuropathologica communications. 2021;9(1):1-11.

[108] La C, Linortner P, Bernstein JD, Cruadhlaoich MAU, Fenesy M, Deutsch GK, et al. Hippocampal CA1 subfield predicts episodic memory impairment in Parkinson's disease. NeuroImage: Clinical. 2019;23:101824.

[109] Risher ML, Sexton HG, Risher WC, Wilson WA, Fleming RL, Madison RD, et al. Adolescent intermittent alcohol exposure: dysregulation of thrombospondins and synapse formation are associated with decreased neuronal density in the adult hippocampus. Alcoholism: Clinical and Experimental Research. 2015;39(12):2403-13.

[110] Moreno-Jiménez EP, Flor-García M, Terreros-Roncal J, Rábano A, Cafini F, Pallas-Bazarra N, et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nature medicine. 2019;25(4):554-60.

[111]Wang X, Michaelis EK. Selective neuronal vulnerability to oxidative stress in the brain. Frontiers in aging neuroscience. 2010;2:12.

[112] Kerchner G, Hess C, Hammond-Rosenbluth K, Xu D, Rabinovici G, Kelley D, et al. Hippocampal CA1 apical neuropil atrophy in mild Alzheimer disease visualized with 7-T MRI. Neurology. 2010;75(15):1381-7.

[113] Moorthi P, Premkumar P, Priyanka R, Jayachandran K, Anusuyadevi M. Pathological changes in hippocampal neuronal circuits underlie age-associated neurodegeneration and memory loss: positive clue toward SAD. Neuroscience. 2015;301:90-105.

[114] Gouthaman P, Vijayalakshmi S, Vijayaraghavan R, Senthilkumar S. Effect of Loranthus longiflorus Extract on Neuronal Damage Induced by Electromagnetic Radiation in Wistar Rats. Indian Journal of Animal Research.1:7.

[115] Sabbatini M, Catalani A, Consoli C, Marletta N, Tomassoni D, Avola R. The hippocampus in spontaneously hypertensive rats: an animal model of vascular dementia? Mechanisms of ageing and development. 2002;123(5):547-59.

[116] Bartsch T, Alfke K, Stingele R, Rohr A, Freitag-Wolf S, Jansen O, et al. Selective affection of hippocampal CA-1 neurons in patients with transient global amnesia without long-term sequelae. Brain. 2006;129(11):2874-84.

[117] Wang J-Y, Xia Q, Chu K-T, Pan J, Sun L-N, Zeng B, et al. Severe global cerebral ischemia-induced programmed necrosis of hippocampal CA1 neurons in rat is prevented by 3-methyladenine: a widely used inhibitor of autophagy. Journal of Neuropathology & Experimental Neurology. 2011;70(4):314-22.

[118] Wang X, Zaidi A, Pal R, Garrett AS, Braceras R, Chen X-w, et al. Genomic and biochemical approaches in the discovery of mechanisms for selective neuronal vulnerability to oxidative stress. BMC neuroscience. 2009;10(1):1-20.

[119] Vivar C, Praag Hv. Running Changes the Brain: the Long and the Short of It. 2017;32(6):410-24.

[120] Kitamura T, Mishina M, Sugiyama H. Enhancement of neurogenesis by running wheel exercises is suppressed in mice lacking NMDA receptor ε1 subunit. Neuroscience Research. 2003;47(1):55-63.

[121] Gao Y, Syed M, Zhao X. Mechanisms underlying the effect of voluntary running on adult hippocampal neurogenesis. 2023;33(4):373-90.

[122] Stranahan AM, Khalil D, Gould E. Running induces widespread structural alterations in the hippocampus and entorhinal cortex. Hippocampus. 2007;17(11):1017-22.

[123] van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proceedings of the National Academy of Sciences of the United States of America. 1999;96(23):13427-31.

[124] Gremmelspacher T, Gerlach J, Hubbe A, Haas CA, Häussler UJFiN. Neurogenic processes are induced by very short periods of voluntary wheel-running in male mice. 2017;11:385.

[125] Sang Z, Wang K, Dong J, Tang LJEJoMC. Alzheimer's disease: updated multi-targets therapeutics are in clinical and in progress. 2022;238:114464.

[126] Aisen PS, Jimenez-Maggiora GA, Rafii MS, Walter S, Raman RJNRN. Early-stage Alzheimer disease: getting trial-ready. 2022;18(7):389-99.

[127] De la Rosa A, Olaso-Gonzalez G, Arc-Chagnaud C, Millan F, Salvador-Pascual A, García-Lucerga C, et al. Physical exercise in the prevention and treatment of Alzheimer's disease. Journal of sport and health science. 2020;9(5):394-404.

[128] Assunção SS, Sperling RA, Ritchie C, Kerwin DR, Aisen PS, Lansdall C, et al. Meaningful benefits: a framework to assess disease-modifying therapies in preclinical and early Alzheimer’s disease. 2022;14(1):1-16.