Neuroprotective Effects of Chronic Resveratrol Treatment and Exercise Training in the 3xTg-AD Mouse Model of Alzheimer’s Disease

Tom L. Broderick; Suhail Rasool; Rongzi Li; Yuxian Zhang; Miranda Anderson; Layla Al-Nakkash; Jeffrey H. Plochocki; Thangiah Geetha; Jeganathan Ramesh Babu

doi:10.3390/ijms21197337

journal article Open Access Oct 04, 2020

Neuroprotective Effects of Chronic Resveratrol Treatment and Exercise Training in the 3xTg-AD Mouse Model of Alzheimer’s Disease

Tom L. Broderick Suhail Rasool Rongzi Li Yuxian Zhang

Miranda Anderson Layla Al-Nakkash

Jeffrey H. Plochocki

Thangiah Geetha

Jeganathan Ramesh Babu

International Journal of Molecular Sciences Vol. 21 No. 19 pp. 7337 · MDPI AG

View at Publisher Save 10.3390/ijms21197337

Abstract

To date, there is no cure or effective treatment for Alzheimer’s disease (AD), a chronic neurodegenerative condition that affects memory, language, and behavior. AD is characterized by neuroinflammation, accumulation of brain amyloid-beta (Aβ) oligomers and neurofibrillary tangles, increased neuronal apoptosis, and loss of synaptic function. Promoting regular exercise and a diet containing polyphenols are effective non-pharmacological approaches that prevent the progression of neurodegenerative diseases. In this study, we measured various conformational toxic species of Aβ and markers of inflammation, apoptosis, endolysosomal degradation, and neuroprotection after 5 months of exercise training (ET), resveratrol (Resv) treatment, or combination treatment in the 3xTg-AD mouse model of AD. Our main results indicate that Resv decreased neuroinflammation and accumulation of Aβ oligomers, increased levels of neurotrophins, synaptic markers, silent information regulator, and decreased markers of apoptosis, autophagy, endolysosomal degradation and ubiquitination in the brains of 3xTg-AD mice. ET improved some markers related to neuroprotection, but when combined with Resv treatment, the benefits achieved were as effective as Resv treatment alone. Our results show that the neuroprotective effects of Resv, ET or Resv and ET are associated with reduced toxicity of Aβ oligomers, suppression of neuronal autophagy, decreased apoptosis, and upregulation of key growth-related proteins.

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References

105

[1]

Sperling "Functional Alterations in Memory Networks in Early Alzheimer’s Disease" Neuromol. Med. (2010) 10.1007/s12017-009-8109-7

[2]

(2020, July 18). World Alzheimer Report 2018. Available online: https://www.alz.co.uk/research/world-report-2018.

[3]

Direct evidence of oxidative injury produced by the Alzheimer's β-Amyloid peptide (1–40) in cultured hippocampal neurons

Marni E. Harris, Kenneth Hensley, D.Allan Butterfield et al.

Experimental Neurology 1995 10.1016/0014-4886(95)90041-1

[4]

Eckert "Soluble beta-amyloid leads to mitochondrial defects in amyloid precursor protein and tau transgenic mice" Neurodegener. Dis. (2008) 10.1159/000113689

[5]

Kolarova "Structure and pathology of tau protein in Alzheimer disease" Int. J. Alzheimers Dis. (2012)

[6]

Klein "Synaptotoxic amyloid-β oligomers: A molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease?" J. Alzheimers Dis. JAD (2013) 10.3233/jad-2012-129039

[7]

Kayed "Molecular mechanisms of amyloid oligomers toxicity" J. Alzheimers Dis. JAD (2013) 10.3233/jad-2012-129001

[8]

The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics

John Hardy, Dennis J. Selkoe

Science 2002 10.1126/science.1072994

[9]

Chen "Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils" Science (2001) 10.1126/science.1062097

[10]

Ferrari "Beta-Amyloid induces paired helical filament-like tau filaments in tissue culture" J. Biol. Chem. (2003) 10.1074/jbc.m308243200

[11]

Wu "Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by A beta oligomers" Neurobiol. Aging (2008) 10.1016/j.neurobiolaging.2007.02.029

[12]

Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models

Lars M. Ittner, Yazi D. Ke, Fabien Delerue et al.

Cell 2010 10.1016/j.cell.2010.06.036

[13]

Chabrier "Soluble aβ promotes wild-type tau pathology in vivo" J. Neurosci. (2012) 10.1523/jneurosci.0172-12.2012

[14]

Pensalfini "Intracellular amyloid and the neuronal origin of Alzheimer neuritic plaques" Neurobiol. Dis. (2014) 10.1016/j.nbd.2014.07.011

[15]

Scarmeas "Physical activity, diet, and risk of Alzheimer disease" JAMA (2009) 10.1001/jama.2009.1144

[16]

Stranahan "Anti-inflammatory effects of physical activity in relationship to improved cognitive status in humans and mouse models of Alzheimer’s disease" Curr. Alzheimer Res. (2012) 10.2174/156720512799015019

[17]

Souza "Neuroprotective effect of physical exercise in a mouse model of Alzheimer’s disease induced by β-amyloid1-40 peptide" Neurotox. Res. (2013) 10.1007/s12640-012-9373-0

[18]

Revilla "Physical exercise protects against Alzheimer’s disease in 3xTg-AD mice" J. Alzheimers Dis. JAD (2011) 10.3233/jad-2011-101635

[19]

Pena "Hippocampal Growth Factor and Myokine Cathepsin B Expression following Aerobic and Resistance Training in 3xTg-AD Mice" Int. J. Chronic Dis. (2020)

[20]

Liu "Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer’s disease mice" J. Neuroinflammation (2020) 10.1186/s12974-019-1653-7

[21]

Kim "Protective effect of exercise training against the progression of Alzheimer’s disease in 3xTg-AD mice" Behav. Brain Res. (2019) 10.1016/j.bbr.2019.112105

[22]

Do, K., Laing, B.T., Landry, T., Bunner, W., Mersaud, N., Matsubara, T., Li, P., Yuan, Y., Lu, Q., and Huang, H. (2018). The effects of exercise on hypothalamic neurodegeneration of Alzheimer’s disease mouse model. PLoS ONE, 13. 10.1371/journal.pone.0190205

[23]

Kim "Exercise Attenuates High-Fat Diet-induced Disease Progression in 3xTg-AD Mice" Med. Sci. Sports Exerc. (2017) 10.1249/mss.0000000000001166

[24]

Li "Resveratrol, a neuroprotective supplement for Alzheimer’s disease" Curr. Pharm. Des. (2012) 10.2174/138161212798919075

[25]

Kim "Protective effects of piceatannol against beta-amyloid-induced neuronal cell death" Ann. N. Y. Acad. Sci. (2007) 10.1196/annals.1397.051

[26]

Karuppagounder "Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer’s disease" Neurochem. Int. (2009) 10.1016/j.neuint.2008.10.008

[27]

Wang "Grape-derived polyphenolics prevent Abeta oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimer’s disease" J. Neurosci. (2008) 10.1523/jneurosci.0364-08.2008

[28]

Capiralla "Resveratrol mitigates lipopolysaccharide- and Aβ-mediated microglial inflammation by inhibiting the TLR4/NF-κB/STAT signaling cascade" J. Neurochem. (2012) 10.1111/j.1471-4159.2011.07594.x

[29]

Ladiwala "Resveratrol selectively remodels soluble oligomers and fibrils of amyloid Abeta into off-pathway conformers" J. Biol. Chem. (2010) 10.1074/jbc.m110.133108

[30]

Rahvar "Effect of oral resveratrol on the BDNF gene expression in the hippocampus of the rat brain" Neurochem. Res. (2011) 10.1007/s11064-010-0396-8

[31]

Shojaei "Differential Effects of Resveratrol on the Expression of Brain-Derived Neurotrophic Factor Transcripts and Protein in the Hippocampus of Rat Brain" Iran. J. Med. Sci. (2017)

[32]

Park "Resveratrol inhibits the proliferation of neural progenitor cells and hippocampal neurogenesis" J. Biol. Chem. (2012) 10.1074/jbc.m112.406413

[33]

Cowansage "Brain-derived neurotrophic factor: A dynamic gatekeeper of neural plasticity" Curr. Mol. Pharmacol. (2010) 10.2174/1874467211003010012

[34]

Esfandiarei "Beneficial effects of resveratrol and exercise training on cardiac and aortic function and structure in the 3xTg mouse model of Alzheimer’s disease" Drug Des. Devel. Ther. (2019) 10.2147/dddt.s196119

[35]

Alkhouli, M.F., Hung, J., Squire, M., Anderson, M., Castro, M., Babu, J.R., Al-Nakkash, L., Broderick, T.L., and Plochocki, J.H. (2019). Exercise and resveratrol increase fracture resistance in the 3xTg-AD mouse model of Alzheimer’s disease. BMC Complement. Altern. Med., 19. 10.1186/s12906-019-2451-6

[36]

Billings "Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice" Neuron (2005) 10.1016/j.neuron.2005.01.040

[37]

Oddo "Triple-transgenic model of Alzheimer’s disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction" Neuron (2003) 10.1016/s0896-6273(03)00434-3

[38]

Zheng "Amyloid β-abrogated TrkA ubiquitination in PC12 cells analogous to Alzheimer’s disease" J. Neurochem. (2015) 10.1111/jnc.13076

[39]

Crews "Role of synucleins in Alzheimer’s disease" Neurotox. Res. (2009) 10.1007/s12640-009-9073-6

[40]

Salminen "Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer’s disease" Prog. Neurobiol. (2012) 10.1016/j.pneurobio.2011.11.005

[41]

Su "Autophagy and p62 in cardiac protein quality control" Autophagy (2011) 10.4161/auto.7.11.17339

[42]

Caccamo "p62 improves AD-like pathology by increasing autophagy" Mol. Psychiatry (2017) 10.1038/mp.2016.139

[43]

Sawda "Resveratrol for Alzheimer’s disease" Ann. N. Y. Acad. Sci. (2017) 10.1111/nyas.13431

[44]

Morris, J.K., Vidoni, E.D., Johnson, D.K., Van Sciver, A., Mahnken, J.D., Honea, R.A., Wilkins, H.M., Brooks, W.M., Billinger, S.A., and Swerdlow, R.H. (2017). Aerobic exercise for Alzheimer’s disease: A randomized controlled pilot trial. PLoS ONE, 12. 10.1371/journal.pone.0170547

[45]

Cass "Alzheimer’s Disease and Exercise: A Literature Review" Curr. Sports Med. Rep. (2017) 10.1249/jsr.0000000000000332

[46]

Heneka "Inflammatory processes in Alzheimer’s disease" J. Neuroimmunol. (2007) 10.1016/j.jneuroim.2006.11.017

[47]

Ospina "Abeta[25-35] peptide and iron promote apoptosis in lymphocytes by an oxidative stress mechanism: Involvement of H2O2, caspase-3, NF-kappaB, p53 and c-Jun" Neurotoxicology (2002) 10.1016/s0161-813x(02)00081-5

[48]

Tansey "Neuroinflammatory mechanisms in Parkinson’s disease: Potential environmental triggers, pathways, and targets for early therapeutic intervention" Exp. Neurol. (2007) 10.1016/j.expneurol.2007.07.004

[49]

Kayed "Astrocytes contain amyloid-β annular protofibrils in Alzheimer’s disease brains" FEBS Lett. (2011) 10.1016/j.febslet.2011.08.027

[50]

Saiko "Resveratrol and its analogs: Defense against cancer, coronary disease and neurodegenerative maladies or just a fad?" Mutat. Res. (2008) 10.1016/j.mrrev.2007.08.004

Showing 50 of 105 references

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Details

Published: Oct 04, 2020
Vol/Issue: 21(19)
Pages: 7337
License: View

Authors

T

Tom L. Broderick

Department of Physiology, College of Graduate Studies, Midwestern University, Glendale, AZ 85308, USA; Laboratory of Diabetes and Exercise Metabolism, College of Graduate Studies, Midwestern University, Glendale, AZ 85308, USA

S

Suhail Rasool

Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA

R

Rongzi Li

Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA

Y

Yuxian Zhang

Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA

M

Miranda Anderson

Laboratory of Diabetes and Exercise Metabolism, College of Graduate Studies, Midwestern University, Glendale, AZ 85308, USA

L

Layla Al-Nakkash

Department of Physiology, College of Graduate Studies, Midwestern University, Glendale, AZ 85308, USA

J

Jeffrey H. Plochocki

Department of Medical Education, University of Central Florida, College of Medicine, 6850 Lake Nona Blvd, Orlando, FL 32827, USA

T

Thangiah Geetha

Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA

J

Jeganathan Ramesh Babu

Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA

Cite This Article

Tom L. Broderick, Suhail Rasool, Rongzi Li, et al. (2020). Neuroprotective Effects of Chronic Resveratrol Treatment and Exercise Training in the 3xTg-AD Mouse Model of Alzheimer’s Disease. International Journal of Molecular Sciences, 21(19), 7337. https://doi.org/10.3390/ijms21197337

Neuroprotective Effects of Chronic Resveratrol Treatment and Exercise Training in the 3xTg-AD Mouse Model of Alzheimer’s Disease

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