Analysis of the Relationship Between Metalloprotease-9 and Tau Protein in Alzheimer's Disease

Mario Hernandes-Alejandro; Sarita Montaño; Charles R Harrington; Claude M Wischik; Andrés Salas-Casas; Pedro Cortes-Reynosa; Eduardo Pérez Salazar; Javier Cazares-Apatiga; Ricardo Apatiga-Perez; Miguel Ángel Ontiveros Torres; George Perry; Mar Pacheco-Herrero; José Luna-Muñoz

doi:10.3233/JAD-200146

Analysis of the Relationship Between Metalloprotease-9 and Tau Protein in Alzheimer's Disease

Mario Hernandes-Alejandro^* (Corresponding Author), Sarita Montaño, Charles R Harrington, Claude M Wischik, Andrés Salas-Casas, Pedro Cortes-Reynosa, Eduardo Pérez Salazar, Javier Cazares-Apatiga, Ricardo Apatiga-Perez, Miguel Ángel Ontiveros Torres, George Perry, Mar Pacheco-Herrero, José Luna-Muñoz

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

Abstract

BACKGROUND: Neurofibrillary tangles (NFTs) and amyloid plaques are the neuropathological hallmarks in brains with Alzheimer's disease (AD). Post-translational modifications of tau, such as phosphorylation and truncation, have been proposed as initiators in the assembly of the abnormal paired helical filaments that constitute the NFTs. Neurons and NFTs are sites of matrix metalloproteinases (MMPs).

OBJECTIVE: The aim of this study was to analyze the relationship of MMP-9 and tau protein in brain samples with AD.

METHODS: This study was performed on brain tissue samples from patients with early, moderate, and late AD. MMPs and tau levels were analyzed by western blot and gelatin-substrate zymography. Immunofluorescence techniques and confocal microscopy were used to analyze the presence of both proteins in NFTs. Further, molecular dynamics simulations (MDS) and protein-protein docking were conducted to predict interaction between MMP-9 and tau protein.

RESULTS: MMP-9 expression was greatest in moderate and late AD, whereas MMP-2 expression was only increased in late-stage AD. Interestingly, confocal microscopy revealed NFTs in which there was co-localization of MMP-9 and tau protein. MDS and protein-protein docking predictions indicate that a high-affinity complex can be formed between MMP-9 and full-length tau protein.

CONCLUSION: These observations provide preliminary evidence of an interaction between these two proteins. Post-translational modifications of tau protein, such as C-terminal truncation or phosphorylation of amino acid residues in the MMP-9 recognition site and conformational changes in the protein, such as folding of the N-terminal sequence over the three-repeat domain, could preclude the interaction between MMP-9 and tau protein during stages of NFT development.

Original language	English
Pages (from-to)	553-569
Number of pages	17
Journal	Journal of Alzheimer's Disease
Volume	76
Issue number	2
DOIs	https://doi.org/10.3233/JAD-200146
Publication status	Published - 21 Jul 2020

Bibliographical note

The authors want to express their gratitude to Héctor Oliver-Hernández for artwork support. We also are grateful to LANCAD for the supercomputer time support. The MDS was performed in the Laboratory of Bioinformatics at FCQB-UAS, and in the Hybrid Cluster Xiuhcoatl (http://clusterhibrido.cinvestav.mx) at CINVESTAV-IPN, México. The authors thank Lester I. Binder† (North Western, Chicago, IL, USA) for the generous gift of mAb (tauC-3), Tec. Amparo Viramontes Pintos of the handling of the brain tissue, and the confocal microscopy unit of CIIDIR Durango, Instituto Politécnico Nacional. We also want to express our gratitude to the Mexican families who donate the brain of the 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†.

The National Polytechnic Institute (IPN), México, Grant 20171962 to M.H.A. and 2018-2019-2A3-208 to J. L-M and M. P-H, supported part of this work.

Keywords

Alzheimer’s disease
matrix metalloproteinase-9
molecular dynamics simulation
protein-protein docking
tau protein
Alzheimer's disease

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Hernandes-Alejandro, M., Montaño, S., Harrington, C. R., Wischik, C. M., Salas-Casas, A., Cortes-Reynosa, P., Pérez Salazar, E., Cazares-Apatiga, J., Apatiga-Perez, R., Ontiveros Torres, M. Á., Perry, G., Pacheco-Herrero, M., & Luna-Muñoz, J. (2020). Analysis of the Relationship Between Metalloprotease-9 and Tau Protein in Alzheimer's Disease. Journal of Alzheimer's Disease, 76(2), 553-569. https://doi.org/10.3233/JAD-200146

Hernandes-Alejandro, M, Montaño, S, Harrington, CR , Wischik, CM, Salas-Casas, A, Cortes-Reynosa, P, Pérez Salazar, E, Cazares-Apatiga, J, Apatiga-Perez, R, Ontiveros Torres, MÁ, Perry, G, Pacheco-Herrero, M & Luna-Muñoz, J 2020, 'Analysis of the Relationship Between Metalloprotease-9 and Tau Protein in Alzheimer's Disease', Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 553-569. https://doi.org/10.3233/JAD-200146

@article{04eaf67f1e1e4239a6ed5bc20d70e6d1,

title = "Analysis of the Relationship Between Metalloprotease-9 and Tau Protein in Alzheimer's Disease",

abstract = "BACKGROUND: Neurofibrillary tangles (NFTs) and amyloid plaques are the neuropathological hallmarks in brains with Alzheimer's disease (AD). Post-translational modifications of tau, such as phosphorylation and truncation, have been proposed as initiators in the assembly of the abnormal paired helical filaments that constitute the NFTs. Neurons and NFTs are sites of matrix metalloproteinases (MMPs).OBJECTIVE: The aim of this study was to analyze the relationship of MMP-9 and tau protein in brain samples with AD.METHODS: This study was performed on brain tissue samples from patients with early, moderate, and late AD. MMPs and tau levels were analyzed by western blot and gelatin-substrate zymography. Immunofluorescence techniques and confocal microscopy were used to analyze the presence of both proteins in NFTs. Further, molecular dynamics simulations (MDS) and protein-protein docking were conducted to predict interaction between MMP-9 and tau protein.RESULTS: MMP-9 expression was greatest in moderate and late AD, whereas MMP-2 expression was only increased in late-stage AD. Interestingly, confocal microscopy revealed NFTs in which there was co-localization of MMP-9 and tau protein. MDS and protein-protein docking predictions indicate that a high-affinity complex can be formed between MMP-9 and full-length tau protein.CONCLUSION: These observations provide preliminary evidence of an interaction between these two proteins. Post-translational modifications of tau protein, such as C-terminal truncation or phosphorylation of amino acid residues in the MMP-9 recognition site and conformational changes in the protein, such as folding of the N-terminal sequence over the three-repeat domain, could preclude the interaction between MMP-9 and tau protein during stages of NFT development.",

keywords = "Alzheimer{\textquoteright}s disease, matrix metalloproteinase-9, molecular dynamics simulation, protein-protein docking, tau protein, Alzheimer's disease",

author = "Mario Hernandes-Alejandro and Sarita Monta{\~n}o and Harrington, {Charles R} and Wischik, {Claude M} and Andr{\'e}s Salas-Casas and Pedro Cortes-Reynosa and {P{\'e}rez Salazar}, Eduardo and Javier Cazares-Apatiga and Ricardo Apatiga-Perez and {Ontiveros Torres}, {Miguel {\'A}ngel} and George Perry and Mar Pacheco-Herrero and Jos{\'e} Luna-Mu{\~n}oz",

note = "The authors want to express their gratitude to H{\'e}ctor Oliver-Hern{\'a}ndez for artwork support. We also are grateful to LANCAD for the supercomputer time support. The MDS was performed in the Laboratory of Bioinformatics at FCQB-UAS, and in the Hybrid Cluster Xiuhcoatl (http://clusterhibrido.cinvestav.mx) at CINVESTAV-IPN, M{\'e}xico. The authors thank Lester I. Binder† (North Western, Chicago, IL, USA) for the generous gift of mAb (tauC-3), Tec. Amparo Viramontes Pintos of the handling of the brain tissue, and the confocal microscopy unit of CIIDIR Durango, Instituto Polit{\'e}cnico Nacional. We also want to express our gratitude to the Mexican families who donate the brain of the loved ones affected with Alzheimer{\textquoteright}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†. The National Polytechnic Institute (IPN), M{\'e}xico, Grant 20171962 to M.H.A. and 2018-2019-2A3-208 to J. L-M and M. P-H, supported part of this work.",

year = "2020",

month = jul,

day = "21",

doi = "10.3233/JAD-200146",

language = "English",

volume = "76",

pages = "553--569",

journal = "Journal of Alzheimer's Disease",

issn = "1387-2877",

publisher = "IOS Press",

number = "2",

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TY - JOUR

T1 - Analysis of the Relationship Between Metalloprotease-9 and Tau Protein in Alzheimer's Disease

AU - Hernandes-Alejandro, Mario

AU - Montaño, Sarita

AU - Harrington, Charles R

AU - Wischik, Claude M

AU - Salas-Casas, Andrés

AU - Cortes-Reynosa, Pedro

AU - Pérez Salazar, Eduardo

AU - Cazares-Apatiga, Javier

AU - Apatiga-Perez, Ricardo

AU - Ontiveros Torres, Miguel Ángel

AU - Perry, George

AU - Pacheco-Herrero, Mar

AU - Luna-Muñoz, José

N1 - The authors want to express their gratitude to Héctor Oliver-Hernández for artwork support. We also are grateful to LANCAD for the supercomputer time support. The MDS was performed in the Laboratory of Bioinformatics at FCQB-UAS, and in the Hybrid Cluster Xiuhcoatl (http://clusterhibrido.cinvestav.mx) at CINVESTAV-IPN, México. The authors thank Lester I. Binder† (North Western, Chicago, IL, USA) for the generous gift of mAb (tauC-3), Tec. Amparo Viramontes Pintos of the handling of the brain tissue, and the confocal microscopy unit of CIIDIR Durango, Instituto Politécnico Nacional. We also want to express our gratitude to the Mexican families who donate the brain of the 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†. The National Polytechnic Institute (IPN), México, Grant 20171962 to M.H.A. and 2018-2019-2A3-208 to J. L-M and M. P-H, supported part of this work.

PY - 2020/7/21

Y1 - 2020/7/21

N2 - BACKGROUND: Neurofibrillary tangles (NFTs) and amyloid plaques are the neuropathological hallmarks in brains with Alzheimer's disease (AD). Post-translational modifications of tau, such as phosphorylation and truncation, have been proposed as initiators in the assembly of the abnormal paired helical filaments that constitute the NFTs. Neurons and NFTs are sites of matrix metalloproteinases (MMPs).OBJECTIVE: The aim of this study was to analyze the relationship of MMP-9 and tau protein in brain samples with AD.METHODS: This study was performed on brain tissue samples from patients with early, moderate, and late AD. MMPs and tau levels were analyzed by western blot and gelatin-substrate zymography. Immunofluorescence techniques and confocal microscopy were used to analyze the presence of both proteins in NFTs. Further, molecular dynamics simulations (MDS) and protein-protein docking were conducted to predict interaction between MMP-9 and tau protein.RESULTS: MMP-9 expression was greatest in moderate and late AD, whereas MMP-2 expression was only increased in late-stage AD. Interestingly, confocal microscopy revealed NFTs in which there was co-localization of MMP-9 and tau protein. MDS and protein-protein docking predictions indicate that a high-affinity complex can be formed between MMP-9 and full-length tau protein.CONCLUSION: These observations provide preliminary evidence of an interaction between these two proteins. Post-translational modifications of tau protein, such as C-terminal truncation or phosphorylation of amino acid residues in the MMP-9 recognition site and conformational changes in the protein, such as folding of the N-terminal sequence over the three-repeat domain, could preclude the interaction between MMP-9 and tau protein during stages of NFT development.

AB - BACKGROUND: Neurofibrillary tangles (NFTs) and amyloid plaques are the neuropathological hallmarks in brains with Alzheimer's disease (AD). Post-translational modifications of tau, such as phosphorylation and truncation, have been proposed as initiators in the assembly of the abnormal paired helical filaments that constitute the NFTs. Neurons and NFTs are sites of matrix metalloproteinases (MMPs).OBJECTIVE: The aim of this study was to analyze the relationship of MMP-9 and tau protein in brain samples with AD.METHODS: This study was performed on brain tissue samples from patients with early, moderate, and late AD. MMPs and tau levels were analyzed by western blot and gelatin-substrate zymography. Immunofluorescence techniques and confocal microscopy were used to analyze the presence of both proteins in NFTs. Further, molecular dynamics simulations (MDS) and protein-protein docking were conducted to predict interaction between MMP-9 and tau protein.RESULTS: MMP-9 expression was greatest in moderate and late AD, whereas MMP-2 expression was only increased in late-stage AD. Interestingly, confocal microscopy revealed NFTs in which there was co-localization of MMP-9 and tau protein. MDS and protein-protein docking predictions indicate that a high-affinity complex can be formed between MMP-9 and full-length tau protein.CONCLUSION: These observations provide preliminary evidence of an interaction between these two proteins. Post-translational modifications of tau protein, such as C-terminal truncation or phosphorylation of amino acid residues in the MMP-9 recognition site and conformational changes in the protein, such as folding of the N-terminal sequence over the three-repeat domain, could preclude the interaction between MMP-9 and tau protein during stages of NFT development.

KW - Alzheimer’s disease

KW - matrix metalloproteinase-9

KW - molecular dynamics simulation

KW - protein-protein docking

KW - tau protein

KW - Alzheimer's disease

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U2 - 10.3233/JAD-200146

DO - 10.3233/JAD-200146

M3 - Article

C2 - 32538846

SN - 1387-2877

VL - 76

SP - 553

EP - 569

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

IS - 2

ER -

Analysis of the Relationship Between Metalloprotease-9 and Tau Protein in Alzheimer's Disease

Abstract

Bibliographical note

Keywords

UN SDGs

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