Abstract
Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a component of the extracellular environment, where it mediates diverse processes including matrix regulation/turnover, inflammation and angiogenesis. Rare TIMP-3 risk alleles and mutations are directly linked with retinopathies such as age-related macular degeneration (AMD) and Sorsby fundus dystrophy, and potentially, through indirect mechanisms, with Alzheimer’s disease. Insights into TIMP-3 activities may be gleaned from studying Sorsby-linked mutations. However, recent findings do not fully support the prevailing hypothesis that a gain of function through the dimerisation of mutated TIMP-3 is responsible for retinopathy. Findings from Alzheimer’s patients suggest a hitherto poorly studied relationship between TIMP-3 and the Alzheimer’s-linked amyloid-beta (Aβ) proteins that warrant further scrutiny. This may also have implications for understanding AMD as aged/diseased retinae contain high levels of Aβ. Findings from TIMP-3 knockout and mutant knock-in mice have not led to new treatments, particularly as the latter does not satisfactorily recapitulate the Sorsby phenotype. However, recent advances in stem cell and in vitro approaches offer novel insights into understanding TIMP-3 pathology in the retina-brain axis, which has so far not been collectively examined. We propose that TIMP-3 activities could extend beyond its hitherto supposed functions to cause age-related changes and disease in these organs.
Highlights
Tissue inhibitors of metalloproteinases (TIMPs) are proteins expressed ubiquitously in the body which play important roles through their ability to reversibly inhibit enzymes belonging to the zinc protease superfamily, predominantly matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs) [1]
Tissue inhibitor of metalloproteinase-3 (TIMP-3) functions extend beyond the extracellular matrix (ECM), targeting several other processes, including inflammation as well as angiogenesis in the senescent retina and brain
The increase in TIMP-3 reported in Alzheimer’s disease (AD) brains has not been reported in other forms of neuropathology, suggesting a specific role for TIMP-3 in AD, possibly through Aβ [85,99]
Summary
Tissue inhibitors of metalloproteinases (TIMPs) are proteins expressed ubiquitously in the body which play important roles through their ability to reversibly inhibit enzymes belonging to the zinc protease superfamily, predominantly matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs) [1]. There is considerable conservation in the amino acid structure of TIMP family members. TIMP-3 is considered to have a predominantly extracellular role, as the protein is capable of binding to the extracellular matrix (ECM) via its N or C- terminal domains [4,5]. TIMP-1, -2 and -4 proteins were considered to predominantly exist in soluble form within the interstitial space of the ECM. The interaction of TIMP-3 with ECM proteoglycans is primarily mediated via its C-terminal domain. We discuss new evidence from our respective laboratories as well as other groups, showing that TIMP-3 activities influence important processes such as tissue remodelling, amyloid-beta (Aβ) pathology and angiogenesis amongst others, and propose that further study could unravel new insights into complex degenerative diseases that have so far eluded effective treatment
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