Abstract
Purpose. Abnormal protein deposits including β-amyloid, found in ageing Bruch's membrane and brain, are susceptible to degradation by matrix metalloproteinases (MMPs). In ageing Bruch's membrane, these MMPs become less effective due to polymerisation and aggregation reactions (constituting the MMP Pathway), a situation much advanced in age-related macular degeneration (AMD). The likely presence of this MMP Pathway in brain with the potential to compromise the degradation of β-amyloid associated with Alzheimer's disease (AD) has been investigated. Methods. Presence of high molecular weight MMP species (HMW1 and HMW2) together with the much larger aggregate termed LMMC was determined by standard zymographic techniques. Centrigugation and gel filtration techniques were used to separate and quantify the distribution between bound and free MMP species. Results. The MMP Pathway, initially identified in Bruch's membrane, was also present in brain tissue. The various MMP species displayed bound-free equilibrium and in AD samples, the amount of bound HMW1 and pro-MMP9 species was significantly reduced (p < 0.05). The abnormal operation of the MMP Pathway in AD served to reduce the degradation potential of the MMP system. Conclusion. The presence and abnormalities of the MMP Pathway in both brain and ocular tissues may therefore contribute to the anomalous deposits associated with AD and AMD.
Highlights
Alzheimer’s disease (AD) and age-related macular degeneration (AMD) are neurodegenerative disorders that share a strong correlation with advancing age and are both characterized by similar extracellular deposits
Whereas AD shows the abundant presence of aggregated amyloid β (Aβ) peptides and hyperphosphorylated tau protein in brain, AMD is characterized by deposition of lipids, lipoproteinaceous debris, and oxidized and damaged extracellular matrix (ECM) components within Bruch’s membrane of the eye [5,6,7]
We have demonstrated the presence of the matrix metalloproteinases (MMPs) Pathway in brain tissue and assessed its operation in donors with AD
Summary
Alzheimer’s disease (AD) and age-related macular degeneration (AMD) are neurodegenerative disorders that share a strong correlation with advancing age and are both characterized by similar extracellular deposits. Whereas AD shows the abundant presence of aggregated Aβ peptides and hyperphosphorylated tau protein in brain, AMD is characterized by deposition of lipids, lipoproteinaceous debris, and oxidized and damaged extracellular matrix (ECM) components within Bruch’s membrane of the eye [5,6,7]. The degradation pathway is mediated by matrix metalloproteinases (MMPs) and primary gelatinase components are MMP2 and MMP9, the former being the constitutive enzyme and the latter the inducible form. These MMPs are released as inactive proenzymes (pro-MMPs) and on activation (by proteolytic cleavage of a small peptide) are capable of digesting all components of an ECM [8,9,10,11]. MMPs are involved in many diverse tissue remodelling activities including wound healing and embryonic development, and increased activities are associated with pathological conditions as varied as cancer, rheumatoid arthritis, and cardiovascular diseases [12,13,14,15,16]
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