Tau Protein Phosphorylated at Threonine-231 Is Expressed Abundantly in the Cerebellum in Prion Encephalopathies

Víctor Manuel  Gómez-López; Amparo Viramontes-Pintos; Miguel Angel Ontiveros-Torres; Linda Garcés-Ramírez; Fidel  De La Cruz-López; Ignacio Villanueva-Fierro; Marely Bravo-Muñoz; Charles Harrington; Sandra Martínez-Robles; Petra  Yescas; Parménides Guadarrama-Ortíz; Mario Hernandes-Alejandro; José Francisco Montiel-Sosa; Mar Pacheco-Herrero; José Luna-Muñoz

doi:10.3233/JAD-201308

Tau Protein Phosphorylated at Threonine-231 Is Expressed Abundantly in the Cerebellum in Prion Encephalopathies

Víctor Manuel Gómez-López, Amparo Viramontes-Pintos, Miguel Angel Ontiveros-Torres, Linda Garcés-Ramírez, Fidel De La Cruz-López, Ignacio Villanueva-Fierro, Marely Bravo-Muñoz, Charles Harrington, Sandra Martínez-Robles, Petra Yescas, Parménides Guadarrama-Ortíz, Mario Hernandes-Alejandro, José Francisco Montiel-Sosa, Mar Pacheco-Herrero, José Luna-Muñoz^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

Background: Transmissible spongiform encephalopathies (TSEs) are rare neurodegenerative disorders that affect animals and humans. Bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeld-Jakob Disease (CJD) in humans belong to this group. The causative agent of TSEs is called “prion”, which corresponds to a pathological form (PrPSc) of a normal cellular protein (PrPC) expressed in nerve cells. PrPSc is resistant to degradation and can induce abnormal folding of PrPC, and TSEs are characterized by extensive spongiosis and gliosis and the presence of PrPSc amyloid plaques. CJD presents initially with clinical symptoms similar to Alzheimer's disease (AD). In AD, tau aggregates and amyloid-β protein plaques are associated with memory loss and cognitive impairment in patients. Objective: In this work, we study the role of tau and its relationship with PrPSc plaques in CJD. Methods: Multiple immunostainings with specific antibodies were carried out and analyzed by confocal microscopy. Results: We found increased expression of the glial fibrillary acidic protein (GFAP) and matrix metalloproteinase (MMP-9), and an exacerbated apoptosis in the granular layer in cases with prion disease. In these cases, tau protein phosphorylated at Thr-231 was overexpressed in the axons and dendrites of Purkinje cells and the extensions of parallel fibers of the cerebellum. Conclusion: We conclude that phosphorylation of tau may be a response to the toxic and inflammatory environment generated by the pathological form of prion.

Original language	English
Pages (from-to)	769-785
Number of pages	17
Journal	Journal of Alzheimer's Disease
Volume	81
Issue number	2
Early online date	2 Apr 2021
DOIs	https://doi.org/10.3233/JAD-201308
Publication status	Published - 18 May 2021

Bibliographical note

ACKNOWLEDGMENTS: The authors want to express their gratitude to the following: Dr. P. Davies † (Albert Einstein College of Medicine, Bronx, NY, USA) and Lester I. Binder † (North Western, Chicago, IL, USA) for the generous gift of mAbs TG-3 and Alz-50, and Tau-1, Tau-5 and Tau-7, respectively; Tec. Amparo Viramontes Pintos for the handling of the brain tissue; support in the confocal microscopy unit of CIIDIR Durango, Instituto Politécnico Nacional; Union Medica University Clinic, Dominican Republic, for their support and collaboration in the development of this research project. We also want to express our gratitude to the Mexican families who have donated the brain of their loved ones affected with Alzheimer's disease and made our research possible. This work is dedicated to the memory of Professor Dr. José Raúl Mena López †. †Deceased.

This work was supported by Fondo Nacional de Ciencia y Tecnologia, FONDOCyT, from the Ministry of Higher Education, Science and Technology, Dominican Republic (2015-3A2-127 to MP-H) and (2018-2019-2A3-208 to JL-M and MP-H).

Keywords

Cerebellum
neuronal death
prion encephalopathy
prion protein
tau protein

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Gómez-López, V. M., Viramontes-Pintos, A., Ontiveros-Torres, M. A., Garcés-Ramírez, L., De La Cruz-López, F., Villanueva-Fierro, I., Bravo-Muñoz, M., Harrington, C., Martínez-Robles, S., Yescas, P., Guadarrama-Ortíz, P., Hernandes-Alejandro, M., Montiel-Sosa, J. F., Pacheco-Herrero, M., & Luna-Muñoz, J. (2021). Tau Protein Phosphorylated at Threonine-231 Is Expressed Abundantly in the Cerebellum in Prion Encephalopathies. Journal of Alzheimer's Disease, 81(2), 769-785. https://doi.org/10.3233/JAD-201308

Gómez-López, VM, Viramontes-Pintos, A, Ontiveros-Torres, MA, Garcés-Ramírez, L, De La Cruz-López, F, Villanueva-Fierro, I, Bravo-Muñoz, M, Harrington, C, Martínez-Robles, S, Yescas, P, Guadarrama-Ortíz, P, Hernandes-Alejandro, M, Montiel-Sosa, JF, Pacheco-Herrero, M & Luna-Muñoz, J 2021, 'Tau Protein Phosphorylated at Threonine-231 Is Expressed Abundantly in the Cerebellum in Prion Encephalopathies', Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 769-785. https://doi.org/10.3233/JAD-201308

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title = "Tau Protein Phosphorylated at Threonine-231 Is Expressed Abundantly in the Cerebellum in Prion Encephalopathies",

abstract = "Background: Transmissible spongiform encephalopathies (TSEs) are rare neurodegenerative disorders that affect animals and humans. Bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeld-Jakob Disease (CJD) in humans belong to this group. The causative agent of TSEs is called “prion”, which corresponds to a pathological form (PrPSc) of a normal cellular protein (PrPC) expressed in nerve cells. PrPSc is resistant to degradation and can induce abnormal folding of PrPC, and TSEs are characterized by extensive spongiosis and gliosis and the presence of PrPSc amyloid plaques. CJD presents initially with clinical symptoms similar to Alzheimer's disease (AD). In AD, tau aggregates and amyloid-β protein plaques are associated with memory loss and cognitive impairment in patients. Objective: In this work, we study the role of tau and its relationship with PrPSc plaques in CJD. Methods: Multiple immunostainings with specific antibodies were carried out and analyzed by confocal microscopy. Results: We found increased expression of the glial fibrillary acidic protein (GFAP) and matrix metalloproteinase (MMP-9), and an exacerbated apoptosis in the granular layer in cases with prion disease. In these cases, tau protein phosphorylated at Thr-231 was overexpressed in the axons and dendrites of Purkinje cells and the extensions of parallel fibers of the cerebellum. Conclusion: We conclude that phosphorylation of tau may be a response to the toxic and inflammatory environment generated by the pathological form of prion.",

keywords = "Cerebellum, neuronal death, prion encephalopathy, prion protein, tau protein",

author = "G{\'o}mez-L{\'o}pez, {V{\'i}ctor Manuel} and Amparo Viramontes-Pintos and Ontiveros-Torres, {Miguel Angel} and Linda Garc{\'e}s-Ram{\'i}rez and {De La Cruz-L{\'o}pez}, Fidel and Ignacio Villanueva-Fierro and Marely Bravo-Mu{\~n}oz and Charles Harrington and Sandra Mart{\'i}nez-Robles and Petra Yescas and Parm{\'e}nides Guadarrama-Ort{\'i}z and Mario Hernandes-Alejandro and Montiel-Sosa, {Jos{\'e} Francisco} and Mar Pacheco-Herrero and Jos{\'e} Luna-Mu{\~n}oz",

note = "ACKNOWLEDGMENTS: The authors want to express their gratitude to the following: Dr. P. Davies † (Albert Einstein College of Medicine, Bronx, NY, USA) and Lester I. Binder † (North Western, Chicago, IL, USA) for the generous gift of mAbs TG-3 and Alz-50, and Tau-1, Tau-5 and Tau-7, respectively; Tec. Amparo Viramontes Pintos for the handling of the brain tissue; support in the confocal microscopy unit of CIIDIR Durango, Instituto Polit{\'e}cnico Nacional; Union Medica University Clinic, Dominican Republic, for their support and collaboration in the development of this research project. We also want to express our gratitude to the Mexican families who have donated the brain of their loved ones affected with Alzheimer's disease and made our research possible. This work is dedicated to the memory of Professor Dr. Jos{\'e} Ra{\'u}l Mena L{\'o}pez †. †Deceased. This work was supported by Fondo Nacional de Ciencia y Tecnologia, FONDOCyT, from the Ministry of Higher Education, Science and Technology, Dominican Republic (2015-3A2-127 to MP-H) and (2018-2019-2A3-208 to JL-M and MP-H).",

year = "2021",

month = may,

day = "18",

doi = "10.3233/JAD-201308",

language = "English",

volume = "81",

pages = "769--785",

journal = "Journal of Alzheimer's Disease",

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publisher = "IOS Press",

number = "2",

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TY - JOUR

T1 - Tau Protein Phosphorylated at Threonine-231 Is Expressed Abundantly in the Cerebellum in Prion Encephalopathies

AU - Gómez-López, Víctor Manuel

AU - Viramontes-Pintos, Amparo

AU - Ontiveros-Torres, Miguel Angel

AU - Garcés-Ramírez, Linda

AU - De La Cruz-López, Fidel

AU - Villanueva-Fierro, Ignacio

AU - Bravo-Muñoz, Marely

AU - Harrington, Charles

AU - Martínez-Robles, Sandra

AU - Yescas, Petra

AU - Guadarrama-Ortíz, Parménides

AU - Hernandes-Alejandro, Mario

AU - Montiel-Sosa, José Francisco

AU - Pacheco-Herrero, Mar

AU - Luna-Muñoz, José

N1 - ACKNOWLEDGMENTS: The authors want to express their gratitude to the following: Dr. P. Davies † (Albert Einstein College of Medicine, Bronx, NY, USA) and Lester I. Binder † (North Western, Chicago, IL, USA) for the generous gift of mAbs TG-3 and Alz-50, and Tau-1, Tau-5 and Tau-7, respectively; Tec. Amparo Viramontes Pintos for the handling of the brain tissue; support in the confocal microscopy unit of CIIDIR Durango, Instituto Politécnico Nacional; Union Medica University Clinic, Dominican Republic, for their support and collaboration in the development of this research project. We also want to express our gratitude to the Mexican families who have donated the brain of their loved ones affected with Alzheimer's disease and made our research possible. This work is dedicated to the memory of Professor Dr. José Raúl Mena López †. †Deceased. This work was supported by Fondo Nacional de Ciencia y Tecnologia, FONDOCyT, from the Ministry of Higher Education, Science and Technology, Dominican Republic (2015-3A2-127 to MP-H) and (2018-2019-2A3-208 to JL-M and MP-H).

PY - 2021/5/18

Y1 - 2021/5/18

N2 - Background: Transmissible spongiform encephalopathies (TSEs) are rare neurodegenerative disorders that affect animals and humans. Bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeld-Jakob Disease (CJD) in humans belong to this group. The causative agent of TSEs is called “prion”, which corresponds to a pathological form (PrPSc) of a normal cellular protein (PrPC) expressed in nerve cells. PrPSc is resistant to degradation and can induce abnormal folding of PrPC, and TSEs are characterized by extensive spongiosis and gliosis and the presence of PrPSc amyloid plaques. CJD presents initially with clinical symptoms similar to Alzheimer's disease (AD). In AD, tau aggregates and amyloid-β protein plaques are associated with memory loss and cognitive impairment in patients. Objective: In this work, we study the role of tau and its relationship with PrPSc plaques in CJD. Methods: Multiple immunostainings with specific antibodies were carried out and analyzed by confocal microscopy. Results: We found increased expression of the glial fibrillary acidic protein (GFAP) and matrix metalloproteinase (MMP-9), and an exacerbated apoptosis in the granular layer in cases with prion disease. In these cases, tau protein phosphorylated at Thr-231 was overexpressed in the axons and dendrites of Purkinje cells and the extensions of parallel fibers of the cerebellum. Conclusion: We conclude that phosphorylation of tau may be a response to the toxic and inflammatory environment generated by the pathological form of prion.

AB - Background: Transmissible spongiform encephalopathies (TSEs) are rare neurodegenerative disorders that affect animals and humans. Bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeld-Jakob Disease (CJD) in humans belong to this group. The causative agent of TSEs is called “prion”, which corresponds to a pathological form (PrPSc) of a normal cellular protein (PrPC) expressed in nerve cells. PrPSc is resistant to degradation and can induce abnormal folding of PrPC, and TSEs are characterized by extensive spongiosis and gliosis and the presence of PrPSc amyloid plaques. CJD presents initially with clinical symptoms similar to Alzheimer's disease (AD). In AD, tau aggregates and amyloid-β protein plaques are associated with memory loss and cognitive impairment in patients. Objective: In this work, we study the role of tau and its relationship with PrPSc plaques in CJD. Methods: Multiple immunostainings with specific antibodies were carried out and analyzed by confocal microscopy. Results: We found increased expression of the glial fibrillary acidic protein (GFAP) and matrix metalloproteinase (MMP-9), and an exacerbated apoptosis in the granular layer in cases with prion disease. In these cases, tau protein phosphorylated at Thr-231 was overexpressed in the axons and dendrites of Purkinje cells and the extensions of parallel fibers of the cerebellum. Conclusion: We conclude that phosphorylation of tau may be a response to the toxic and inflammatory environment generated by the pathological form of prion.

KW - Cerebellum

KW - neuronal death

KW - prion encephalopathy

KW - prion protein

KW - tau protein

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DO - 10.3233/JAD-201308

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JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

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Tau Protein Phosphorylated at Threonine-231 Is Expressed Abundantly in the Cerebellum in Prion Encephalopathies

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