Moderate Exercise and Insulin in Combination Protect Against Brain Atrophy and Weight Loss by Modulation of Glucose Metabolism in Rat Model of Alzheimer' Disease

Radfar, Forough; Shahbazi, Mehdi; Tahmasebi Boroujeni, Shahzad; Arabameri, Elaheh; Farahmandfar, Maryam

doi:10.22059/sshr.2024.369689.1116

Moderate Exercise and Insulin in Combination Protect Against Brain Atrophy and Weight Loss by Modulation of Glucose Metabolism in Rat Model of Alzheimer' Disease

Document Type : Research Paper

Authors

¹ Department of Behavioral and Cognitive Sciences in Sports, Faculty of Sport Sciences and Health , University of Tehran

² Tehran University of Medical Sciences

10.22059/sshr.2024.369689.1116

Abstract

Background: Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, is characterized by amyloid-beta (Aβ) plaque accumulation, neurofibrillary tangles, neuronal death, inflammation, and oxidative stress.
Aim: We investigated the effects of treadmill exercise and intranasal insulin on spatial memory, blood glucose level, and Physical growth indicators including weight, head circumference, and tail length.
Materials and Methods: Seventy-two male Wistar rats, aged 8 weeks were into 9 gtoups at random (control, Sham, Aβ, Aβ + EX, Aβ +PINS, Aβ + INST, Aβ + EX + PINS, Aβ + EX + INST, and Aβ + EX + PINS + INST). We discovered that rats receiving Aβ25-35 had impaired spatial memory, which was associated with weight loss, brain growth retardation, Tail Length, and elevated blood glucose levels. Data from each trial was statistically analyzed using IBM SPSS
Statistics 22 software, Two-way ANOVA, and post-hoc analysis Tukey test. The cut-off for statistical significance was P≤0.05.
Results: Our results show that the improvement of spatial memory due to the improvement of metabolism and growth indicators can be affected by pretreatment exercise and intranasal insulin. Also, exercise training and intranasal insulin improved spatial memory and prevented brain growth retardation, increased blood glucose, weight loss, and tail length in animals treated with Aβ25-35.
Conclusion: Exercise can amplify the positive benefits of intranasal insulin treatment on memory. The results of our research showed that exercise and insulin can prevent brain growth retardation and prevent spatial memory disorders by improving glucose metabolismy.

Keywords

References

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[8] Šerbedžija P, Ishii DN. "Insulin and insulin-like growth factor prevent brain atrophy and cognitive impairment in diabetic rats". Indian J Endocrinol Metab. 2012; 16(3): 601-10. doi: 0.4103/2230-8210.105578.

[9] Zhao N, Xu B. "The beneficial effect of exercise against Alzheimer’s disease may result from improved brain glucose metabolism". Neurosci Lett. 2021; 763(June): 18-21. doi: 10.1186/s40035-023-00364-y.

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[14] Colcombe SJ, Kramer AF, Erickson KI, Scalf P, Mcauley E, Cohen NJ, et al. "Cardiovascular fitness , cortical plasticity, and aging". PNAS. 2004; 101(9): 3316-21. doi: 10.1073/pnas.0400266101.

[15] Draganski B, May A. "Training-induced structural changes in the adult human brain". Behav Brain Res J. 2008; 192: 137-42. doi: 10.1016/j.bbr.2008.02.015.

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[18] Karimi-Zandi L, Zahmatkesh M, Hassanzadeh G, Hosseinzadeh S. "Increment of CSF fractalkine-positive microvesicles preceded the spatial memory impairment in amyloid beta neurotoxicity". Cytokine. 2022; 160: 156050. https://doi.org/10.1016/j.cyto.2022.156050.

[19] Song Y, Li P, Liu L, Bortolini C, Dong M. "Nanostructural differentiation and toxicity of Amyloid-β25-35 aggregates ensue from distinct secondary conformation". Sci Rep. 2018; 8(1): 2-10. http://dx.doi.org/10.1038/s41598-017-19106-y.

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[22] Rajasekar N, Nath C, Hanif K, Shukla R. "Intranasal insulin exerts beneficial effects by improving cerebral blood flow, Nrf-2 expression and BDNF in STZ (ICV) induced memory-impaired rats". Life Sci. 2016; 173: 1-10. http://dx.doi.org/10.1016/j.lfs.2016.09.020.

[23] Wang R, Zhang Y, Li J, Zhang C. "Resveratrol ameliorates spatial learning memory impairment induced by Aβ1–42 in rats". Neuroscience. 2017; 344: 39-47. http://dx.doi.org/10.1016/j.neuroscience.2016.08.051.

[24] Palop JJ, Mucke L. "Amyloid-β-induced neuronal dysfunction in Alzheimer’s disease: From synapses toward neural networks". Nat Neurosci. 2010; 13(7): 812-8. http://dx.doi.org/10.1038/nn.2583.

[25] Li B, Liang F, Ding X, Yan Q, Zhao Y, Zhang X, et al. "Interval and continuous exercise overcome memory deficits related to β-Amyloid accumulation through modulating mitochondrial dynamics". Behav Brain Res. 2019; 376(800): 1-10. doi: 10.1016/j.bbr.2019.112171.

[26] Kumar V, Kim S, Bishayee K. "Dysfunctional glucose metabolism in Alzheimer’s disease onset and potential pharmacological interventions". Int J Mol Sci Rev. 2022; 23(9540): 1-16. doi: 10.3390/ijms23179540.

[27] Dao AT, Zagaar MA, Alkadhi KA. "Moderate treadmill exercise protects synaptic plasticity of the dentate gyrus and related signaling cascade in a rat model of Alzheimer’s disease". Mol Neurobiological. 2014; 52(3): 14-6. doi: 10.1007/s12035-014-8916-1.

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[29] Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, et al. "Brain insulin receptors and spatial memory". J Biol Chem. 1999; 274(49): 34893-902. doi: 10.1074/jbc.274.49.34893.

[30] Pascoal TA, Mathotaarachchi S, Kang MS, Mohaddes S, Shin M, Park AY, et al. "Aβ-induced vulnerability propagates via the brain’s default mode network". Nat Commun. 2019; 10(2353): 1-13. http://dx.doi.org/10.1038/s41467-019-10217-w.

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[33] Camandola S. "Brain metabolism in health, aging , and neurodegeneration". EMBO J. 2017; 24: 1-19. doi: 10.15252/embj.201695810.

[34] Berchicci M, Lucci G, Russo F Di. "Benefits of physical exercise on the aging brain : The role of the prefrontal cortex". Journals Gerontol. 2013; 68(11): 1337-41. doi: 10.1186/s12974-022-02401-5.

[35] Mattson MP. "Energy intake and exercise as determinants of brain health and vulnerability to injury and disease". Cell Metab. 2012; 16(6): 706-22. http://dx.doi.org/10.1016/j.cmet.2012.08.012.

[36] Rui QP, Xiao FW, Fei Fei P, Weizhe Zh, Jiaming Sh, Xiaoqun G. "Regular exercise enhances cognitive function and intracephalic GLUT expression in Alzheimer’s Disease model mice". J Alzheimer’s Dis. 2019; 20: 1-14. doi: 10.3233/JAD-190328.

[37] Leonard WR, Marcia RNU. "Evolutionary perspectives on human nutrition : The influence of brain and body size on diet and metabolism". Am J Hum Biol. 1994; 6(3): 77-88. doi: 10.1002/ajhb.1310060111.

[38] Ravussin E. "A neat way to control weight ? How to create a spin current". Science. 2005; 307(10): 2004-6. doi: 10.1126/science.1108597.

[39] Bruehl H, Wolf OT, Sweat V, Tirsi A, Richardson S, Convit A. "Modifiers of cognitive function and brain structure in middle-aged and elderly individuals with Type 2 Diabetes Mellitus". Brain Res 2009; 64(3): 186-94. http://dx.doi.org/10.1016/j.brainres.2009.05.032.

[40] Enzinger C, Fazekas F, Matthews PM, Ropele S, Schmidt H, Smith S, et al. "Risk factors for progression of brain atrophy in aging Six-year follow-up of normal subjects". Neurology. 2005; 64: 1704-11. doi: 10.1212/01.WNL.0000161871.83614.BB.

[41] LaFerla FM, Green KN, Oddo S. "Intracellular amyloid-β in Alzheimer’s disease". Nat Rev Neurosci. 2007; 8(7): 499-509. doi: 10.1038/nrn2168.

[42] Simioni C, Zauli G, Martelli AM, Vitale M, Gonelli A, Neri LM. "Oxidative stress : role of physical exercise and antioxidant nutraceuticals in adulthood and aging". Oncotarget. 2018; 9(24): 17181-98. doi: 10.18632/oncotarget.24729.

[43] Pathological A, Aging B, García-mesa Y, Colie S, Corpas R, Cristòfol R, et al. "Oxidative stress is a central target for physical exercise neuroprotection against pathological brain aging". Biol Sci. 2015; 71: 1-11. doi: 10.1093/gerona/glv005.

[44] Luo L, Dai J, Guo S, Lu A, Gao X, Gu Y, et al. "Lysosomal proteolysis is associated with exercise- induced improvement of mitochondrial quality control in aged hippocampus". Journals Gerontol Biol Sci. 2017; 1-10. doi: 10.1093/gerona/glw242.

[45] Endocrinology D, Statistics B, Clinic M, Ruegsegger GN, Manjunatha S, Summer P, et al. "Insulin deficiency and intranasal insulin alter brain mitochondrial function : A potential factor for dementia in diabetes". The FASEB Journal. 2019; 1-15. http://dx.doi.org/10.1096/fj.201802043R.

[46] Heppner FL, Ransohoff RM, Becher B. "Immune attack : The role of inflammation in Alzheimer disease". Nat Publ Gr. 2015; 16(6): 358-72. http://dx.doi.org/10.1038/nrn3880.

[47] Chang Y, Hung L, Chen Y, Wang W. "Insulin reduces in fl ammation by regulating the activation of the NLRP3 In fl ammasome". Front Immunol. 2021; 11: 1-11. doi: 10.3389/fimmu.2020.587229.

[48] Park S, Kim T, Sung Y, Park Y, Kim M, Shin M. "Treadmill exercise ameliorates short-term memory impairment by suppressing hippocampal neuroinflammation in poloxamer- 407-induced hyperlipidemia rats". Int Neurourol J. 2021; 25(Suppl 2): 81-9. doi: 10.5213/inj.2142342.171.

[49] Giacobbo BL, Doorduin J, Klein HC, Dierckx RAJO, Bromberg E, Vries EFJ De. "Brain-derived neurotrophic factor in brain disorders : Focus on neuroinflammation". Mol Neurobiol. 2019; 56: 3295-312. doi: 10.1007/s12035-018-1283-6.

[50] Brabazon F, Wilson CM, Jaiswal S, Reed J, Frey WH, Byrnes KR. "Intranasal insulin treatment of an experimental model of moderate traumatic brain injury". J Cereb Blood Flow Metab. 2017; 37(9): 3203-18. doi: 10.1177/0271678X16685106.

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Moderate Exercise and Insulin in Combination Protect Against Brain Atrophy and Weight Loss by Modulation of Glucose Metabolism in Rat Model of Alzheimer' Disease

References

[1] Abubakar MB, Sanusi KO, Ugusman A, Mohamed W, Kamal H, Ibrahim NH, et al. "Alzheimer’s disease: An update and insights into pathophysiology". Front Aging Neurosci. 2022; 14: 1-16. doi: 10.3389/fnagi.2022.742408 .

[2] Ledig C, Schuh A, Guerrero R, Heckemann RA, Rueckert D. "Structural brain imaging in Alzheimer’s disease and mild cognitive impairment: Biomarker analysis and shared morphometry database". Sci Rep. 2018; 8(1): 1-17. doi: 10.1038/s41598-018-29295-9 .

[3] Mrdjen D, Fox EJ, Bukhari SA, Montine KS, Bendall SC, Montine TJ. "The basis of cellular and regional vulnerability in Alzheimer’s disease". Acta Neuropathol. 2019; 138(5): 729-49. https://doi.org/10.1007/s00401-019-02054-4.

[4] Huang X, Zhao X, Cai Y, Wan Q. "The cerebral changes induced by exercise interventions in people with mild cognitive impairment and Alzheimer’s disease: A systematic review". Arch Gerontol Geriatr. 2022; 98: 1-9. doi: 10.1016/j.archger.2021.104547.

[5] White H, Pieper C, Schmader K DM. "The association of weight change in Alzheimer’s disease with severity of disease and mortality : A longitudinal analysis. J Am Geriatr Soc. 1998; 46(6): 1223-7. doi: 10.1111/j.1532-5415.1998.tb04537.x.

[6] Johnson DK, Wilkins CH. "Accelerated weight loss may precede diagnosis in alzheimer disease". Arch Neurol. 2014; 63(9): 1312-7. doi: 10.1001/archneur.63.9.1312 .

[7] Burns JM, Johnson DK, Watts A, Swerdlow RH, Brooks WM. "Lean mass is reduced in early alzheimer’s disease and associated with brain atrophy". Arch Neurol. 2011; 67(4): 428-33. doi: 10.1001/archneurol.2010.38.

[8] Šerbedžija P, Ishii DN. "Insulin and insulin-like growth factor prevent brain atrophy and cognitive impairment in diabetic rats". Indian J Endocrinol Metab. 2012; 16(3): 601-10. doi: 0.4103/2230-8210.105578.

[9] Zhao N, Xu B. "The beneficial effect of exercise against Alzheimer’s disease may result from improved brain glucose metabolism". Neurosci Lett. 2021; 763(June): 18-21. doi: 10.1186/s40035-023-00364-y.

[10] Do K, Laing BT, Landry T, Bunner W, Mersaud N, Matsubara T, et al. "The effects of exercise on hypothalamic neurodegeneration of Alzheimer’s disease mouse model". PLoS One. 2018; 3: 1-17. doi: 10.1371/journal.pone.0190205.

[11] Mendez MF. "Early-onset alzheimer’s disease : Nonamnestic subtypes and type 2 AD". Arch Med Res. 2012; 43(8): 677-85. http://dx.doi.org/10.1016/j.arcmed.2012.11.009. doi: 10.1016/j.arcmed.2012.11.009.

[12] Tobia C, Ebersole JL, Novak MJ. "Caloric restriction and chronic inflammatory diseases". Oral Dis. 2012; 18: 16-31. doi: 10.1111/j.1601-0825.2011.01830.x.

[13] Colcombe SJ, Erickson KI, Raz N, Webb AG, Cohen NJ, Mcauley E, et al. "Aerobic fitness reduces brain tissue loss in aging humans". J Gerontol. 2003; 58(2): 176-80. doi: 10.1093/gerona/58.2.m176.

[14] Colcombe SJ, Kramer AF, Erickson KI, Scalf P, Mcauley E, Cohen NJ, et al. "Cardiovascular fitness , cortical plasticity, and aging". PNAS. 2004; 101(9): 3316-21. doi: 10.1073/pnas.0400266101.

[15] Draganski B, May A. "Training-induced structural changes in the adult human brain". Behav Brain Res J. 2008; 192: 137-42. doi: 10.1016/j.bbr.2008.02.015.

[16] Erickson KI, Kramer AF. "Aerobic exercise effects on cognitive and neural plasticity in older adults". Br J Sport Med. 2008; 43: 22-4. doi: 10.1016/j.bbr.2008.02.015.

[17] Colcombe SJ, Erickson KI, Scalf PE, Kim JS, Prakash R, Mcauley E, et al. "Aerobic exercise training increases brain volume in aging humans". J Gerontol. 2006; 61(11): 1166-70. doi: 10.1093/gerona/61.11.1166.

[18] Karimi-Zandi L, Zahmatkesh M, Hassanzadeh G, Hosseinzadeh S. "Increment of CSF fractalkine-positive microvesicles preceded the spatial memory impairment in amyloid beta neurotoxicity". Cytokine. 2022; 160: 156050. https://doi.org/10.1016/j.cyto.2022.156050.

[19] Song Y, Li P, Liu L, Bortolini C, Dong M. "Nanostructural differentiation and toxicity of Amyloid-β25-35 aggregates ensue from distinct secondary conformation". Sci Rep. 2018; 8(1): 2-10. http://dx.doi.org/10.1038/s41598-017-19106-y.

[20] Khodadadi D, Gharakhanlou R, Naghdi N, Salimi M, Azimi M, Shahed A. "Treadmill exercise ameliorates spatial learning and memory deficits through improving the clearance of peripheral and central amyloid-Beta Levels 1". Neurochem Res. 2018. http://dx.doi.org/10.1007/s11064-018-2571-2.

[21] Azimi M, Gharakhanlou R, Naghdi N, Peptides DK. "Moderate treadmill exercise ameliorates amyloid-β-induced learning and memory impairment, possibly via increasing AMPK activity and up-regulation of the PGC-1α". Elsevier. 2017 Apr; 102: 78-88. doi: 10.1016/j.peptides.2017.12.027.

[22] Rajasekar N, Nath C, Hanif K, Shukla R. "Intranasal insulin exerts beneficial effects by improving cerebral blood flow, Nrf-2 expression and BDNF in STZ (ICV) induced memory-impaired rats". Life Sci. 2016; 173: 1-10. http://dx.doi.org/10.1016/j.lfs.2016.09.020.

[23] Wang R, Zhang Y, Li J, Zhang C. "Resveratrol ameliorates spatial learning memory impairment induced by Aβ1–42 in rats". Neuroscience. 2017; 344: 39-47. http://dx.doi.org/10.1016/j.neuroscience.2016.08.051.

[24] Palop JJ, Mucke L. "Amyloid-β-induced neuronal dysfunction in Alzheimer’s disease: From synapses toward neural networks". Nat Neurosci. 2010; 13(7): 812-8. http://dx.doi.org/10.1038/nn.2583.

[25] Li B, Liang F, Ding X, Yan Q, Zhao Y, Zhang X, et al. "Interval and continuous exercise overcome memory deficits related to β-Amyloid accumulation through modulating mitochondrial dynamics". Behav Brain Res. 2019; 376(800): 1-10. doi: 10.1016/j.bbr.2019.112171.

[26] Kumar V, Kim S, Bishayee K. "Dysfunctional glucose metabolism in Alzheimer’s disease onset and potential pharmacological interventions". Int J Mol Sci Rev. 2022; 23(9540): 1-16. doi: 10.3390/ijms23179540.

[27] Dao AT, Zagaar MA, Alkadhi KA. "Moderate treadmill exercise protects synaptic plasticity of the dentate gyrus and related signaling cascade in a rat model of Alzheimer’s disease". Mol Neurobiological. 2014; 52(3): 14-6. doi: 10.1007/s12035-014-8916-1.

[29] Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, et al. "Brain insulin receptors and spatial memory". J Biol Chem. 1999; 274(49): 34893-902. doi: 10.1074/jbc.274.49.34893.

[30] Pascoal TA, Mathotaarachchi S, Kang MS, Mohaddes S, Shin M, Park AY, et al. "Aβ-induced vulnerability propagates via the brain’s default mode network". Nat Commun. 2019; 10(2353): 1-13. http://dx.doi.org/10.1038/s41467-019-10217-w.

[33] Camandola S. "Brain metabolism in health, aging , and neurodegeneration". EMBO J. 2017; 24: 1-19. doi: 10.15252/embj.201695810.

[34] Berchicci M, Lucci G, Russo F Di. "Benefits of physical exercise on the aging brain : The role of the prefrontal cortex". Journals Gerontol. 2013; 68(11): 1337-41. doi: 10.1186/s12974-022-02401-5.

[35] Mattson MP. "Energy intake and exercise as determinants of brain health and vulnerability to injury and disease". Cell Metab. 2012; 16(6): 706-22. http://dx.doi.org/10.1016/j.cmet.2012.08.012.

[36] Rui QP, Xiao FW, Fei Fei P, Weizhe Zh, Jiaming Sh, Xiaoqun G. "Regular exercise enhances cognitive function and intracephalic GLUT expression in Alzheimer’s Disease model mice". J Alzheimer’s Dis. 2019; 20: 1-14. doi: 10.3233/JAD-190328.

[37] Leonard WR, Marcia RNU. "Evolutionary perspectives on human nutrition : The influence of brain and body size on diet and metabolism". Am J Hum Biol. 1994; 6(3): 77-88. doi: 10.1002/ajhb.1310060111.

[38] Ravussin E. "A neat way to control weight ? How to create a spin current". Science. 2005; 307(10): 2004-6. doi: 10.1126/science.1108597.

[39] Bruehl H, Wolf OT, Sweat V, Tirsi A, Richardson S, Convit A. "Modifiers of cognitive function and brain structure in middle-aged and elderly individuals with Type 2 Diabetes Mellitus". Brain Res 2009; 64(3): 186-94. http://dx.doi.org/10.1016/j.brainres.2009.05.032.

[40] Enzinger C, Fazekas F, Matthews PM, Ropele S, Schmidt H, Smith S, et al. "Risk factors for progression of brain atrophy in aging Six-year follow-up of normal subjects". Neurology. 2005; 64: 1704-11. doi: 10.1212/01.WNL.0000161871.83614.BB.

[41] LaFerla FM, Green KN, Oddo S. "Intracellular amyloid-β in Alzheimer’s disease". Nat Rev Neurosci. 2007; 8(7): 499-509. doi: 10.1038/nrn2168.

[42] Simioni C, Zauli G, Martelli AM, Vitale M, Gonelli A, Neri LM. "Oxidative stress : role of physical exercise and antioxidant nutraceuticals in adulthood and aging". Oncotarget. 2018; 9(24): 17181-98. doi: 10.18632/oncotarget.24729.

[43] Pathological A, Aging B, García-mesa Y, Colie S, Corpas R, Cristòfol R, et al. "Oxidative stress is a central target for physical exercise neuroprotection against pathological brain aging". Biol Sci. 2015; 71: 1-11. doi: 10.1093/gerona/glv005.

[44] Luo L, Dai J, Guo S, Lu A, Gao X, Gu Y, et al. "Lysosomal proteolysis is associated with exercise- induced improvement of mitochondrial quality control in aged hippocampus". Journals Gerontol Biol Sci. 2017; 1-10. doi: 10.1093/gerona/glw242.

[45] Endocrinology D, Statistics B, Clinic M, Ruegsegger GN, Manjunatha S, Summer P, et al. "Insulin deficiency and intranasal insulin alter brain mitochondrial function : A potential factor for dementia in diabetes". The FASEB Journal. 2019; 1-15. http://dx.doi.org/10.1096/fj.201802043R.

[46] Heppner FL, Ransohoff RM, Becher B. "Immune attack : The role of inflammation in Alzheimer disease". Nat Publ Gr. 2015; 16(6): 358-72. http://dx.doi.org/10.1038/nrn3880.

[47] Chang Y, Hung L, Chen Y, Wang W. "Insulin reduces in fl ammation by regulating the activation of the NLRP3 In fl ammasome". Front Immunol. 2021; 11: 1-11. doi: 10.3389/fimmu.2020.587229.

[48] Park S, Kim T, Sung Y, Park Y, Kim M, Shin M. "Treadmill exercise ameliorates short-term memory impairment by suppressing hippocampal neuroinflammation in poloxamer- 407-induced hyperlipidemia rats". Int Neurourol J. 2021; 25(Suppl 2): 81-9. doi: 10.5213/inj.2142342.171.

[49] Giacobbo BL, Doorduin J, Klein HC, Dierckx RAJO, Bromberg E, Vries EFJ De. "Brain-derived neurotrophic factor in brain disorders : Focus on neuroinflammation". Mol Neurobiol. 2019; 56: 3295-312. doi: 10.1007/s12035-018-1283-6.

[50] Brabazon F, Wilson CM, Jaiswal S, Reed J, Frey WH, Byrnes KR. "Intranasal insulin treatment of an experimental model of moderate traumatic brain injury". J Cereb Blood Flow Metab. 2017; 37(9): 3203-18. doi: 10.1177/0271678X16685106.

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Statistics

[5] White H, Pieper C, Schmader K DM. "The association of weight change in Alzheimer’s disease with severity of disease and mortality : A longitudinal analysis. J Am Geriatr Soc. 1998; 46(6): 1223-7. doi: 10.1111/j.1532-5415.1998.tb04537.x.

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Volume 16, Issue 1
January 2024
Pages 1-13