Longevity Briefs: Could Targeting This Enzyme Prevent Cognitive Decline?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Some degree of cognitive decline is unfortunately inevitable with age, but the extent of this decline can be greatly modified by lifestyle factors. Diet is one such factor, with studies suggesting that obesity is linked to a higher risk of cognitive impairment and even dementia later in life. The mechanisms that connect cognitive decline, ageing and obesity together are less clear. Learning more about these mechanisms could prove very beneficial if they offer us new molecular targets to preserve cognitive function in older age.

In this study, researchers investigate one potential key player, an enzyme known as membrane type 1-matrix metalloproteinase (MT1-MMP). This enzyme sits within the cell membrane and digests the structural meshwork of proteins that hold our cells together, allowing some cell types to move through tissues unimpeded. However, previous work by these researchers had shown that MT1-MMP also has metabolic effects. Inhibiting MT1-MMP appeared to reduce cholesterol levels, reduce body fat and improve sensitivity to the blood sugar-lowering hormone insulin. Since MT1-MMP levels increase with age, the researchers wondered if it could represent a link between ageing, obesity and cognitive decline.

The discovery:

The researchers conducted several experiments, primarily using mice. They found that the activity of MT1-MMP was elevated in the brains of aged mice, and these mice also had higher levels of neuroinflammation (inflammation in the brain). However, suppressing inflammation with a drug reduced MT1-MMP activity in the brain to levels comparable to those in young mice, suggesting a link between neuroinflammation and MT1-MMP.

To test whether MT1-MMP was a meaningful contributor to cognitive decline or just a side effect of neuroinflammation, the researchers looked at mice that were genetically deficient in MT1-MMP. They found that while these mice had just as much neuroinflammation when they grew old as normal mice, their cognitive function as assessed by spatial learning and memory tests was significantly better. The researchers then did something interesting: they took blood plasma from old (18 months) mice (and therefore containing higher levels of inflammatory molecules) and infused it into normal young (2 months) mice and young MT1-MMP-deficient mice. They found that when they did this, the cognitive function of the normal mice was negatively impacted, but the cognitive function of the MT1-MMP deficient mice was not. This suggested that MT1-MMP was at least partially responsible for the effects of neuroinflammation on cognitive function in old age.

Given the aforementioned link between MT1-MMP and obesity, the researchers wanted to see what would happen if they targeted MT1-MMP in obese mice. Young mice were fed a high-fat diet for 9 weeks so that they became obese. They were then given either a control treatment or a gene therapy to inhibit MT1-MMP expression. Just as in the case of old mice, the treated mice had significantly improved cognitive performance compared to the controls, but levels of neuroinflammation were the same. This suggested that MT1-MMP also mediated the relationship between obesity and cognitive impairment in young mice.

To further confirm their findings and perhaps make them more translatable to humans, the researchers also tested an MT1-MMP blocking drug (Ro 28-2653) and an anti-MT1-MMP antibody (3A) and found similar results to those described above. They also showed that altering MT1-MMP activity worked both ways: if they genetically increased MT1-MMP levels in young mice, their cognitive function declined.

The implications:

These findings suggest that MT1-MMP is a common mediator between obesity, ageing and cognitive impairment, potentially making it a valuable target if these findings turn out to apply to humans. But how does this enzyme promote cognitive decline in the first place? The researchers were able to shed some light on the mechanism as well. It seems that MT1-MMP is cleaving a receptor in the hippocampus called GPR158. This receptor responds to osteocalcin, a hormone that plays an important role in preserving cognition by keeping neurons alive and promoting the growth of new neurons. When overactive, MT1-MMP essentially shuts down this cognition-boosting pathway, so targeting this interaction is another possibility.