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