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

Article type: Research Article

Authors: Hernandes-Alejandro, Mario^{a; *} | Montaño, Sarita^b | Harrington, Charles R.^c | Wischik, Claude M.^c | Salas-Casas, Andrés^d | Cortes-Reynosa, Pedro^e | Pérez Salazar, Eduardo^e | Cazares-Apatiga, Javier^f | Apatiga-Perez, Ricardo^{g; k} | Ontiveros Torres, Miguel Ángel^h | Perry, Georgeⁱ | Pacheco-Herrero, Mar^j | Luna-Muñoz, José^k

Affiliations: [a] Departamento de Bioingeniería, Unidad Profesional Interdisciplinaria de Biotecnología del Instituto Politécnico Nacional (UPIBI-IPN), Gustavo A. Madero, México | [b] Laboratorio de Modelado Molecular y Bioinformática de la Facultad de Ciencias-Químico Biológicas de la Universidad Autónoma de Sinaloa, México | [c] School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK | [d] Instituto de Ciencias de la Salud, Área Académica de Gerontología Universidad Autónoma del Estado de Hidalgo, México | [e] Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (Instituto Politécnico Nacional), Gustavo A. Madero, México | [f] Laboratorio de Biología Molecular y Bioseguridad Nivel 3, Centro Médico Naval, CDMX, México | [g] Escuela Nacional de Ciencias Biológicas, Depto. Fisiología, Instituto Politécnico Nacional, CDMX, Mexico | [h] School of Engineering and Science, Tecnológico de Monterrey, Toluca, México | [i] Department of Biology, University of Texas at San Antonio, San Antonio, TX, USA | [j] School of Medicine, Faculty of Health Sciences, Pontificia Universidad Catolica Madre y Maestra, Dominican Republic | [k] National Dementia BioBank, Ciencias Biológicas, Facultad de Estudios Superiores, Cuautitlán campo 1, UNAM, Estado de México, México

Correspondence: [*] Correspondence to: Mario Hernandes-Alejandro, Departamento de Bioingeniería, Unidad Profesional Interdisciplinaria de Biotecnología (UPIBI-IPN), Av. Acueducto 550, La laguna Ticomán, 07340, CDMX, México. E-mail: mhernandes@ipn.mx.

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

DOI: 10.3233/JAD-200146

Journal: Journal of Alzheimer's Disease, vol. 76, no. 2, pp. 553-569, 2020