MMP-14 Levels May Serve as Biomarker and Therapeutic Target in FAP Patients

Matrix metalloprotease-14 (MMP-14) is a novel biomarker for therapy follow-up, as well as a potential therapeutic target in familial amyloidotic polyneuropathy (FAP), said researchers in Portugal.

Their study, “MMP-14 overexpression correlates with the neurodegenerative process in familial amyloidotic polyneuropathy,” appeared in the journal Disease Models and Mechanisms.

FAP is characterized by the misfolding and deposition of a mutant protein called transthyretin (TTR) into nerves of the peripheral nervous system (PNS).

MMPs are a group of proteins that are expressed in response to either an injury or a neurological disease. Levels of one particular MMP, called MMP-14, are elevated in Alzheimer’s and other neurodegenerative and neuroinflammatory diseases in studies that looked at both mouse models and human biopsies.

In fact, higher levels of MMP-14 correlated with regions of deposits of mutant protein aggregates in Alzheimer’s disease models.

Researchers set out to determine the expression levels of MMP-14 in FAP mouse models and tissue samples from FAP patients that have the TTR V30M mutation — the most common mutation associated with FAP — in order to determine whether MMP-14 could be used a biomarker for neurodegeneration.

The results showed that MMP-14 is indeed overexpressed in human FAP-affected nerves, and levels were correlated with mutant TTR swpoaira. Researchers further proved this link by showing that MMP-14 is increased in the sciatic nerves of mouse model of FAP. Levels of MMP-14 rose with increasing amounts of TTR deposits.

Then, researchers showed that levels of MMP-14 in the peripheral nervous system decreased when treated with an anti-inflammatory drug or by reducing TTR production, indicating that the inflammatory response and TTR are involved in increasing levels of MMP-14.

Moreover, MMP-14 levels were increased in Schwann cells — a type of nerve cells affected in FAP — when the cells were incubated with protein aggregates. This result showed a direct relationship between the presence of protein aggregates and an increase in MMP-14 levels.

Finally, researchers showed that MMP-14 in the plasma of FAP patients increases as the disease progresses.

While the exact role of MMP-14 is unclear, the authors write, “the demonstration of increased MMP-14 in the periphery, together with its augmented levels in plasma from FAP patients, especially in advanced stages of disease, denote a correlation between this MMP and neurodegeneration, highlighting its potential role as a novel disease biomarker or even as a promising future therapeutic target.”