Therapeutic role of MSCs-derived exosomes for Alzheimer's disease

Kamal, Sara Mostafa; Wahba, Sanaa M.R.; Mostafa, Aliaa R.H.

doi:10.21608/jsrs.2020.129933

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	Therapeutic role of MSCs-derived exosomes for Alzheimer's disease
Article 3, Volume 37, Part 2 (Biological Sciences), Spring 2020, Page 47-59 PDF (1.32 MB)
Document Type: Original Article
DOI: 10.21608/jsrs.2020.129933
Authors
Sara Mostafa Kamal^* ¹; Sanaa M.R. Wahba²; Aliaa R.H. Mostafa³
¹Zoology department; Faculty of Women for Arts, Science and Education – Ain Shams University.
²Zoology department, Faculty of Women for Arts, Science and Education, Ain Shams University.
³Basic Science department, Faculty of Oral and Dental Medicine, Future University.
Abstract
The discovery of mesenchymal stem cell-derived exosomes (MSCs-derived exosomes) has shed a new light in the development of disease-modifying treatments for Alzheimer (AD). The present study is an attempt to investigate the influence of these extracellular vesicles (exosomes) in Alz therapy. A total of 38 adult female albino Wistar rats were randomly assigned to the following groups: Control group (C) of 8 rats given saline; Alzheimer’s group (Alz) of 15 ovariectomized animals inoculated orally with AlCl₃ (17mg/Kg b.wt/day) for 2 months after 6 weeks of surgical operation and 15 Alzheimer’s disease-induced rats treated (i.v) with (10⁷ MSCs-derived exosomes/rat/week). After 2 and 4 weeks animals were sacrificed by ether inhalation anesthesia where brains were removed and processed for histological investigation by Hx&E and biochemical analysis for measuring β-Amyloid 1-42 and Brain derived neurotrophic factor (BDNF) levels.
Keywords
Alzheimer (Alz); Mesenchymal stem cells (MSCs); Exosomes


References
[1] M.M. Said, G.A. Elmenoufy, "The possible neurotherapeutic effects of Mesenchymal stem cells on AlCl₃-inducedAlzheimer's disease in adult albino rats", OSR-JPBS (2015) 10(5):33-40. [2] Y. Tang, M.W. Lutz, Y.Xing, "A systems-based model of Alzheimer's disease", Alzheimers Dement.(2019)15(1):168-171. [3] F. Kametani, M. Hasegawa, "Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's disease",Front Neurosci.(2018)12: 12-25. [4] N.R. Naidu, S. Bhat, U. Dsouza,"Effect of long term administration of aluminum chloride on oxidative stress and acetylcholinesterase activity in rat brains", IJPBS(2013) 3(1):616-622. [5] S.M.R. Wahba, A.S. Darwish, S.M. Kamal, "Ceria-containing uncoated and coated hydroxyapatite-based galantaminenanocomposites for formidable treatment of Alzheimer’s disease in ovariectomized albino-rat model", Mater Sci Eng C Mater Biol Appl.(2016) 65:151-163. [6] S.M. Kamal, 2015 M.Sc. Thesis "Galantamine bioactivity improvement in rat brain using various novel nano-drug delivery systems as therapy for Alzheimer's disease", (Women's college for Arts, Sc. and Edu., Ain Shams University). [7] G. Li, R. Bi, D. Zhang, M. Xu, R. Luo, D. Wang, Y. Fang, T. Li, C. Zhang, Y. Yao, "Female-specific effect of the BDNF gene on Alzheimer's disease", Neuro Biol Aging. (2017) 53(192): 11-19. [8] M.L. Giuffrida, A. Copani, E. Rizzarelli, "A promising connection between BDNF and Alzheimer’s disease", Aging (Albany NY), (2018) 10(8): 1791–1792. [9] M. Alipour, S.M.Nabavi, L. Arab, M. Vosough, H. Pakdaman, E. Ehsani, K. Shahpasand, "Stem cell therapy in Alzheimer's disease: possible benefits and limiting drawbacks", Mol. Biol. Rep.(2019) 46(1):1425-1446. [10] J.K. Lee, H.K.Jin, J.S. Bae, "Bone marrow-derived mesenchymal stem cells attenuate amyloid β-induced memory impairment and apoptosis by inhibiting neuronal cell death", Curr. Alzheimer Res.(2010) 7(6):540-548. [11] A. Luarte, L.F. Bátiz, U. Wyneken,C. Lafourcade, "Potential therapies by stem cell-derived exosomes in CNS diseases: focusing on the neurogenic niche", Stem Cells Int., (2016) ID: 5736059. [12] Z. Cai, M. Xiao,S.H. Quazi,Z. Ke, "Exosomes: a novel therapeutic target for Alzheimer’s disease?", Neural Regen. Res. (2018) 13(5):930-935. [13] L.C. Liew, T. Katsuda, L. Gailhouste, H. Nakagama, T. Ochiya, "Mesenchymal stem cell-derived extracellular vesicles: a glimmer of hope in treating Alzheimer’s disease", Int. Immunol. (2017) 29(1):11-19. [14] H. Kothmaier, D. Rohrer, E. Stacher, F.Quehenberger, K.F.Becker, H.H. Popper, "Comparison of formalin-free tissue fixatives: a proteomic study testing their application for routine pathology and research", Arch. Pathol. Lab Med. (2011)135(6): 744-752. [15] J. Schulze, O. Kaiser, G. Paasche, H. Lamm, A. Pich, A. Hoffmann, T. Lenarz, A. Warnecke, " Effect of hyperbaric oxygen on BDNF-release and neuroprotection: Investigations with human mesenchymal stem cells and genetically modified NIH3T3 fibroblasts as putative cell therapeutics", PLoS One. (2017) 12(5): e0178182. [16] A.Mokbel, O. ElTookhy , A.A.Shamaa , D.Sabry, L.Rashed, A.Mostafa, “Homing and efficacy of intra-articular injection of autologous mesenchymal stem cells in experimental chondral defects in dogs” Clin Exp Rheumatol. (2011) 29:275–284. [17] F. Torad, M. Amer, A. Shamaa, O. El-Tookhy, D. Sabry, L. Rashed, M. Abd El Hamid, S. Mahfouz, D. Gharib, “Long Term Evaluation of Human Umbilical Cord Blood Mesenchymal Stem Cells in the Management of Total Coronary Occlusion (Experimental Study in Dogs)” Asian J. Anim. Sci. (2015) 9 (6): 266-279. [18] E. GATTI, N.D. VIRGILIO, M. S. MAGLI, “PREDIERI, INTEGRATING SENSORY ANALYSIS AND HEDONIC EVALUATION FOR APPLE QUALITY ASSESSMENT” J. Food Qual.(2011) 34:126–132. [19] A. Othman, R. Mubarak, M. Sameer, D. Sabry, “Fibroblast growth factor-6 enhances CDK2 and MAKT expression in microvesicles derived from human stem cells extracted from exfoliated deciduous teeth” F1000. (2019) 7:610-622. [20] MNT,(2014):http://www.medicalnewstoday.com/images/articles/159442-alzheimers-brain-neurons.jpg. [21] B.A. Berihu, M. Afwerk, Y.G. Debeb, A. Gebreslassie, "Review on Histological and Functional Effect of Aluminium Chloride on Cerebral Cortex of the Brain", IJPSR (2015) 6(8): 1105-1116. [22] A.M. Salem, H.H. Ahmed, H.M. Atta, M.A. Ghazy, H.A. Aglan, "Potential of bone marrow mesenchymal stem cells in management of Alzheimer's disease in female rats", Cell Biol Int.(2014)38(12):1367-1383. [23] A. Caplan, D. Correa, "The MSC: an injury drugstore",Cell Stem Cell. (2011) 8;9(1):11-15. [24] J.Y. Shin, H.J.Park, H.N.Kim, S.H.Oh, J.S.Bae, H.J.Ha, P.H. Lee, "Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models", Autophagy(2014) 10(1):32-44. [25] L. Jiang, H. Dong, H. Cao, X. Ji, S. Luan, J. Liu, "Exosomes in Pathogenesis, Diagnosis, and Treatment of Alzheimer’s Disease", Med Sci Monit.(2019) 25: 3329–3335. [26] M.T. Harting, A.K. Srivastava, S. Zhaorigetu, H. Bair, K.S.Prabhakara, N.E. Toledano Furman, J.V.Vykoukal, K.A. Ruppert, J.R.Cox CS, S.D. Olson, "Inflammation-Stimulated Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Inflammation", J. Stem Cells (2018) 36(1):79-90. [1] M.M. Said, G.A. Elmenoufy, "The possible neurotherapeutic effects of Mesenchymal stem cells on AlCl₃-inducedAlzheimer's disease in adult albino rats", OSR-JPBS (2015) 10(5):33-40. [2] Y. Tang, M.W. Lutz, Y.Xing, "A systems-based model of Alzheimer's disease", Alzheimers Dement.(2019)15(1):168-171. [3] F. Kametani, M. Hasegawa, "Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's disease",Front Neurosci.(2018)12: 12-25. [4] N.R. Naidu, S. Bhat, U. Dsouza,"Effect of long term administration of aluminum chloride on oxidative stress and acetylcholinesterase activity in rat brains", IJPBS(2013) 3(1):616-622. [5] S.M.R. Wahba, A.S. Darwish, S.M. Kamal, "Ceria-containing uncoated and coated hydroxyapatite-based galantaminenanocomposites for formidable treatment of Alzheimer’s disease in ovariectomized albino-rat model", Mater Sci Eng C Mater Biol Appl.(2016) 65:151-163. [6] S.M. Kamal, 2015 M.Sc. Thesis "Galantamine bioactivity improvement in rat brain using various novel nano-drug delivery systems as therapy for Alzheimer's disease", (Women's college for Arts, Sc. and Edu., Ain Shams University). [7] G. Li, R. Bi, D. Zhang, M. Xu, R. Luo, D. Wang, Y. Fang, T. Li, C. Zhang, Y. Yao, "Female-specific effect of the BDNF gene on Alzheimer's disease", Neuro Biol Aging. (2017) 53(192): 11-19. [8] M.L. Giuffrida, A. Copani, E. Rizzarelli, "A promising connection between BDNF and Alzheimer’s disease", Aging (Albany NY), (2018) 10(8): 1791–1792. [9] M. Alipour, S.M.Nabavi, L. Arab, M. Vosough, H. Pakdaman, E. Ehsani, K. Shahpasand, "Stem cell therapy in Alzheimer's disease: possible benefits and limiting drawbacks", Mol. Biol. Rep.(2019) 46(1):1425-1446. [10] J.K. Lee, H.K.Jin, J.S. Bae, "Bone marrow-derived mesenchymal stem cells attenuate amyloid β-induced memory impairment and apoptosis by inhibiting neuronal cell death", Curr. Alzheimer Res.(2010) 7(6):540-548. [11] A. Luarte, L.F. Bátiz, U. Wyneken,C. Lafourcade, "Potential therapies by stem cell-derived exosomes in CNS diseases: focusing on the neurogenic niche", Stem Cells Int., (2016) ID: 5736059. [12] Z. Cai, M. Xiao,S.H. Quazi,Z. Ke, "Exosomes: a novel therapeutic target for Alzheimer’s disease?", Neural Regen. Res. (2018) 13(5):930-935. [13] L.C. Liew, T. Katsuda, L. Gailhouste, H. Nakagama, T. Ochiya, "Mesenchymal stem cell-derived extracellular vesicles: a glimmer of hope in treating Alzheimer’s disease", Int. Immunol. (2017) 29(1):11-19. [14] H. Kothmaier, D. Rohrer, E. Stacher, F.Quehenberger, K.F.Becker, H.H. Popper, "Comparison of formalin-free tissue fixatives: a proteomic study testing their application for routine pathology and research", Arch. Pathol. Lab Med. (2011)135(6): 744-752. [15] J. Schulze, O. Kaiser, G. Paasche, H. Lamm, A. Pich, A. Hoffmann, T. Lenarz, A. Warnecke, " Effect of hyperbaric oxygen on BDNF-release and neuroprotection: Investigations with human mesenchymal stem cells and genetically modified NIH3T3 fibroblasts as putative cell therapeutics", PLoS One. (2017) 12(5): e0178182. [16] A.Mokbel, O. ElTookhy , A.A.Shamaa , D.Sabry, L.Rashed, A.Mostafa, “Homing and efficacy of intra-articular injection of autologous mesenchymal stem cells in experimental chondral defects in dogs” Clin Exp Rheumatol. (2011) 29:275–284. [17] F. Torad, M. Amer, A. Shamaa, O. El-Tookhy, D. Sabry, L. Rashed, M. Abd El Hamid, S. Mahfouz, D. Gharib, “Long Term Evaluation of Human Umbilical Cord Blood Mesenchymal Stem Cells in the Management of Total Coronary Occlusion (Experimental Study in Dogs)” Asian J. Anim. Sci. (2015) 9 (6): 266-279. [18] E. GATTI, N.D. VIRGILIO, M. S. MAGLI, “PREDIERI, INTEGRATING SENSORY ANALYSIS AND HEDONIC EVALUATION FOR APPLE QUALITY ASSESSMENT” J. Food Qual.(2011) 34:126–132. [19] A. Othman, R. Mubarak, M. Sameer, D. Sabry, “Fibroblast growth factor-6 enhances CDK2 and MAKT expression in microvesicles derived from human stem cells extracted from exfoliated deciduous teeth” F1000. (2019) 7:610-622. [20] MNT,(2014):http://www.medicalnewstoday.com/images/articles/159442-alzheimers-brain-neurons.jpg. [21] B.A. Berihu, M. Afwerk, Y.G. Debeb, A. Gebreslassie, "Review on Histological and Functional Effect of Aluminium Chloride on Cerebral Cortex of the Brain", IJPSR (2015) 6(8): 1105-1116. [22] A.M. Salem, H.H. Ahmed, H.M. Atta, M.A. Ghazy, H.A. Aglan, "Potential of bone marrow mesenchymal stem cells in management of Alzheimer's disease in female rats", Cell Biol Int.(2014)38(12):1367-1383. [23] A. Caplan, D. Correa, "The MSC: an injury drugstore",Cell Stem Cell. (2011) 8;9(1):11-15. [24] J.Y. Shin, H.J.Park, H.N.Kim, S.H.Oh, J.S.Bae, H.J.Ha, P.H. Lee, "Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models", Autophagy(2014) 10(1):32-44. [25] L. Jiang, H. Dong, H. Cao, X. Ji, S. Luan, J. Liu, "Exosomes in Pathogenesis, Diagnosis, and Treatment of Alzheimer’s Disease", Med Sci Monit.(2019) 25: 3329–3335. [26] M.T. Harting, A.K. Srivastava, S. Zhaorigetu, H. Bair, K.S.Prabhakara, N.E. Toledano Furman, J.V.Vykoukal, K.A. Ruppert, J.R.Cox CS, S.D. Olson, "Inflammation-Stimulated Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Inflammation", J. Stem Cells (2018) 36(1):79-90.
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Therapeutic role of MSCs-derived exosomes for Alzheimer's disease

[4] N.R. Naidu, S. Bhat, U. Dsouza,"Effect of long term administration of aluminum chloride on oxidative stress and acetylcholinesterase activity in rat brains", IJPBS(2013) 3(1):616-622.

[8] M.L. Giuffrida, A. Copani, E. Rizzarelli, "A promising connection between BDNF and Alzheimer’s disease", Aging (Albany NY), (2018) 10(8): 1791–1792.

[9] M. Alipour, S.M.Nabavi, L. Arab, M. Vosough, H. Pakdaman, E. Ehsani, K. Shahpasand, "Stem cell therapy in Alzheimer's disease: possible benefits and limiting drawbacks", Mol. Biol. Rep.(2019) 46(1):1425-1446.

[10] J.K. Lee, H.K.Jin, J.S. Bae, "Bone marrow-derived mesenchymal stem cells attenuate amyloid β-induced memory impairment and apoptosis by inhibiting neuronal cell death", Curr. Alzheimer Res.(2010) 7(6):540-548.

[13] L.C. Liew, T. Katsuda, L. Gailhouste, H. Nakagama, T. Ochiya, "Mesenchymal stem cell-derived extracellular vesicles: a glimmer of hope in treating Alzheimer’s disease", Int. Immunol. (2017) 29(1):11-19.

[14] H. Kothmaier, D. Rohrer, E. Stacher, F.Quehenberger, K.F.Becker, H.H. Popper, "Comparison of formalin-free tissue fixatives: a proteomic study testing their application for routine pathology and research", Arch. Pathol. Lab Med. (2011)135(6): 744-752.

[18] E. GATTI, N.D. VIRGILIO, M. S. MAGLI, “PREDIERI, INTEGRATING SENSORY ANALYSIS AND HEDONIC EVALUATION FOR APPLE QUALITY ASSESSMENT” J. Food Qual.(2011) 34:126–132.

[19] A. Othman, R. Mubarak, M. Sameer, D. Sabry, “Fibroblast growth factor-6 enhances CDK2 and MAKT expression in microvesicles derived from human stem cells extracted from exfoliated deciduous teeth” F1000. (2019) 7:610-622.

[20] MNT,(2014):http://www.medicalnewstoday.com/images/articles/159442-alzheimers-brain-neurons.jpg.

[22] A.M. Salem, H.H. Ahmed, H.M. Atta, M.A. Ghazy, H.A. Aglan, "Potential of bone marrow mesenchymal stem cells in management of Alzheimer's disease in female rats", Cell Biol Int.(2014)38(12):1367-1383.

[23] A. Caplan, D. Correa, "The MSC: an injury drugstore",Cell Stem Cell. (2011) 8;9(1):11-15.

[24] J.Y. Shin, H.J.Park, H.N.Kim, S.H.Oh, J.S.Bae, H.J.Ha, P.H. Lee, "Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models", Autophagy(2014) 10(1):32-44.

[25] L. Jiang, H. Dong, H. Cao, X. Ji, S. Luan, J. Liu, "Exosomes in Pathogenesis, Diagnosis, and Treatment of Alzheimer’s Disease", Med Sci Monit.(2019) 25: 3329–3335.

[26] M.T. Harting, A.K. Srivastava, S. Zhaorigetu, H. Bair, K.S.Prabhakara, N.E. Toledano Furman, J.V.Vykoukal, K.A. Ruppert, J.R.Cox CS, S.D. Olson, "Inflammation-Stimulated Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Inflammation", J. Stem Cells (2018) 36(1):79-90.

[4] N.R. Naidu, S. Bhat, U. Dsouza,"Effect of long term administration of aluminum chloride on oxidative stress and acetylcholinesterase activity in rat brains", IJPBS(2013) 3(1):616-622.

[8] M.L. Giuffrida, A. Copani, E. Rizzarelli, "A promising connection between BDNF and Alzheimer’s disease", Aging (Albany NY), (2018) 10(8): 1791–1792.

[9] M. Alipour, S.M.Nabavi, L. Arab, M. Vosough, H. Pakdaman, E. Ehsani, K. Shahpasand, "Stem cell therapy in Alzheimer's disease: possible benefits and limiting drawbacks", Mol. Biol. Rep.(2019) 46(1):1425-1446.

[10] J.K. Lee, H.K.Jin, J.S. Bae, "Bone marrow-derived mesenchymal stem cells attenuate amyloid β-induced memory impairment and apoptosis by inhibiting neuronal cell death", Curr. Alzheimer Res.(2010) 7(6):540-548.

[13] L.C. Liew, T. Katsuda, L. Gailhouste, H. Nakagama, T. Ochiya, "Mesenchymal stem cell-derived extracellular vesicles: a glimmer of hope in treating Alzheimer’s disease", Int. Immunol. (2017) 29(1):11-19.

[14] H. Kothmaier, D. Rohrer, E. Stacher, F.Quehenberger, K.F.Becker, H.H. Popper, "Comparison of formalin-free tissue fixatives: a proteomic study testing their application for routine pathology and research", Arch. Pathol. Lab Med. (2011)135(6): 744-752.

[18] E. GATTI, N.D. VIRGILIO, M. S. MAGLI, “PREDIERI, INTEGRATING SENSORY ANALYSIS AND HEDONIC EVALUATION FOR APPLE QUALITY ASSESSMENT” J. Food Qual.(2011) 34:126–132.

[19] A. Othman, R. Mubarak, M. Sameer, D. Sabry, “Fibroblast growth factor-6 enhances CDK2 and MAKT expression in microvesicles derived from human stem cells extracted from exfoliated deciduous teeth” F1000. (2019) 7:610-622.

[20] MNT,(2014):http://www.medicalnewstoday.com/images/articles/159442-alzheimers-brain-neurons.jpg.

[22] A.M. Salem, H.H. Ahmed, H.M. Atta, M.A. Ghazy, H.A. Aglan, "Potential of bone marrow mesenchymal stem cells in management of Alzheimer's disease in female rats", Cell Biol Int.(2014)38(12):1367-1383.

[23] A. Caplan, D. Correa, "The MSC: an injury drugstore",Cell Stem Cell. (2011) 8;9(1):11-15.

[24] J.Y. Shin, H.J.Park, H.N.Kim, S.H.Oh, J.S.Bae, H.J.Ha, P.H. Lee, "Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models", Autophagy(2014) 10(1):32-44.

[25] L. Jiang, H. Dong, H. Cao, X. Ji, S. Luan, J. Liu, "Exosomes in Pathogenesis, Diagnosis, and Treatment of Alzheimer’s Disease", Med Sci Monit.(2019) 25: 3329–3335.

[26] M.T. Harting, A.K. Srivastava, S. Zhaorigetu, H. Bair, K.S.Prabhakara, N.E. Toledano Furman, J.V.Vykoukal, K.A. Ruppert, J.R.Cox CS, S.D. Olson, "Inflammation-Stimulated Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Inflammation", J. Stem Cells (2018) 36(1):79-90.