For years, Dad had a night job. By day, he ran our family’s retail lumberyard. By night, he ran a mouse relocation program. Our house was full of mice. They scampered through the attic and ran down plumbing and electrical ducts, nabbing cotton balls and Kleenex to build their nests. They got into our food, and left droppings along the baseboard.
The situation came to a head when my mother went into the kitchen to get a plastic bag full of garbage she had left on the counter. “There was a mouse sitting inside the bag, stuffing his face,” she says. She called Dad into the kitchen. He carefully closed the bag, carried it outside, and let the mouse go.
That night, my father brought home a small Havahart trap, baited it with peanut butter, and set it in the laundry room. A quivering brown mouse was in the cage the next morning. On his way to work, Dad drove his passenger down a dirt road, and released him in the woods.
Dad reset the trap that night, and another mouse was there in the morning. This went on for months – almost every morning, another mouse. And almost every morning, Dad would head down the dirt road to his mouse drop-off spot.
“They’ve posted a sign,” he joked, “free peanut butter and a ride.” My parents kept a tally - after four months, Dad had transported 123 mice. They seemed to be multiplying faster than he could clear them out.
Breaking Down Beta Amyloid
Scientists think the same thing may be happening with beta amyloid, the protein that makes up the plaques found in Alzheimer’s. The protein is constantly produced by the body, then cleared from the brain. It may be that in people with Alzheimer’s, the beta amyloid is building up faster than it can be eliminated, and the excess protein is toxic to brain cells.
Researchers have found several enzymes that break down beta amyloid, including insulin degrading enzyme (IDE). Increasing the amount of these substances in the body could help speed up the elimination of excess beta amyloid.
Dr. Jin-Moo Lee, Assistant Professor of Neurology at Washington University School of Medicine in St. Louis has shown that another enzyme called matrix metalloprotease-9 (MMP-9) also degrades beta amyloid. Dr. Lee found that MMP-9 is able to break down the fibrils that make up the plaques found in Alzheimer’s. MMP-9 and other enzymes break down a free-floating kind of beta amyloid that hasn’t formed into plaques. But in Dr. Lee’s lab, the other enzymes didn’t seem to degrade fibrils the way MMP-9 did. These results suggest that MMP-9, already found in the body, may be helpful in clearing plaques from the brain.
There’s more evidence that the enzyme may help regulate beta amyloid levels. Dr. Lee and his colleagues found that turning off the gene for MMP-9 in mice increased the levels of beta amyloid in their brains.
MMP-9’s Role In Other Diseases
Harnessing MMP-9 to break down beta amyloid will be a delicate task. High levels of the enzyme are associated with cancer and arthritis. Even worse in terms of dementia, Dr. Lee has shown that high levels of MMP-9 near blood vessel walls in the brain are associated with cerebral amyloid angiopathy (CAA). In CAA, beta amyloid is deposited on blood vessel walls in the brain. The walls then thicken, harden and crack, allowing blood to leak out into the surrounding tissue. My father’s autopsy showed severe CAA, and it’s likely that the disease and resulting microbleeds caused his dementia. He died last year of a massive hemorrhagic stroke, probably due to CAA.
So MMP-9 may clear Alzheimer’s plaques, but may also be involved in CAA and brain hemorrhages. Is MMP-9 good or bad for the brain?
“MMP-9 is neither ‘good’ nor ‘bad,’ Dr. Lee says, “but may have different responses and activities in different cells and different locations. We have hypothesized that MMP-9 may play a role in weakening the vessel wall in CAA (though this is far from proven)…. We have shown that MMP-9 and -2 can degrade Abeta [beta amyloid] in the brain. These are two different locations and two different activities.”
The fact that increased levels of MMP-9 have been found in the brains of ischemic stroke patients provided a clue to MMP-9’s role in brain hemorrhages. “MMP-9 is upregulated after ischemic stroke,” Dr. Lee explains, “and likely plays a role in converting an ischemic stroke into a hemorrhagic stroke (by weakening the vessel wall). This is why it is so intriguing that MMP-9 is upregulated in CAA vessels, with the thought that CAA vessels may have increased MMP-9 which might eventually lead to weakened vessels.”
Dr. Lee is working to confirm the role of MMP-9 in CAA. He has a study underway to see if lowering MMP-9 levels in mice with CAA reduces the frequency of brain hemorrhages. “This data will be far more convincing,” he says.
More Research Needed
Adding to the uncertainty of MMP-9’s role in dementia, it’s not clear what effect breaking down the beta amyloid fibrils will have. “Again, this may be "good" or "bad," Dr. Lee explains. “Recent reports suggest that smaller aggregates of Abeta (oligomers) may be toxic or inhibit neurotransmission. It is possible that MMP-9 may break down fibrils into these smaller aggregates, which might be even more toxic than fibrils. On the other hand, it is possible that MMP-9 could degrade both fibrils and oligomers rendering them non-toxic. We are currently investigating this.”
It’s also not clear whether drugs designed to increase or decrease levels of MMP-9 could stop brain degeneration and dementia, or what any side effects would be. One possibility for therapy stems from the fact that MMP-9, like many other enzymes, requires the presence of zinc to work. So in theory, reducing the amount of zinc in the body via chelation therapy might inactivate MMP-9 and reduce damage to blood vessel walls. It’s unclear what this might do to the beta amyloid plaques in other areas of the brain, though, and there could be severe side effects. “Removing zinc would likely be detrimental to other systems,” says Dr. Lee.
The connection of MMP-9 to both Alzheimer’s and CAA is intriguing, but still murky. More research is needed before any treatments can be developed. “I think we are far from therapies at this point,” Dr. Lee says. “One must remember that at this level of research, we are trying to understand molecular mechanisms, and we are somewhat removed from therapies. However, our goal is to identify potential targets for the development of therapies. It’s too early to say whether MMP-9 will provide us with viable targets, but therapies to ameliorate disease are always on our minds.”