Alzheimer’s is still one of the biggest medical challenges of our century, since we are facing a disease with a very important incidence and above all that entails a large number of social problems around it. Here research over the decade has focused on the accumulation of protein plaques beta-amyloid in the brain to explain it. However, the scientific community has begun to pay much more attention to an equally devastating factor: neuroinflammation.
A new gene. Science continues to advance and one of the latest discoveries that has been made lies in the APOE4 genewhich is a known risk factor for Alzheimer’s disease. And it is no wonder, since people who inherit this variant have a much higher probability of developing the disease, and often do so at younger ages.
But now a research team has been investigating exactly why having this genetic variant predisposes one to Alzheimer’s, and the answer appears to lie in chronic inflammation. More specifically, in APOE4 carriersthe brain’s immune system overreacts, creating a toxic environment that damages neurons and accelerates cognitive decline. And at the center of this inflammatory storm, researchers have indicated to the enzyme cPLA2 as the main culprit.
It’s a challenge. Knowing that cPLA2 plays a crucial role in the inflammatory cascade associated with Alzheimer’s, the objective is logically set turn it off permanently. However, inhibiting enzymes in the brain is not an easy task, since the brain is very well protected by the blood-brain barrier, which acts as a true customs control that allows only some very selected elements to pass through. That is why creating a drug that passes through it without causing side effects in other parts of the body is a great challenge.
The strategies. To reach this goal, science is now doing computer simulations of thousands of molecules to be able to find those with the exact shape and properties to “fit” into the cPLA2 enzyme and deactivate it. Once this ‘key’ that fits the enzyme that looks like a lock is identified, candidate compounds can be refined for testing in animal models.
Until now, research already has several selective cPLA2 inhibitors that have proven to be powerful and capable of penetrating the brain, making it possible to reduce neuroinflammation in the models studied.
Personalized medicine. The study, supported by multiple leading institutions such as the National Institute on Aging and the Alzheimer’s Drug Discovery Foundation, is not only relevant for the design of the new drugs, but also for its personalized medicine approach.
Looking back, clinical trials for Alzheimer’s have treated all patients equally, often resulting in million-dollar failures. But now, by targeting these new cPLA2 inhibitors specifically at neuroinflammation fueled by the APOE4 gene, scientists are creating tailored treatments for the most biologically vulnerable patients. Although we are still in a very early phase of research, it may take years to see a tangible result.
Images | Robina Weermeijer
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