In Alzheimer’s disease two pathological proteins accumulate in the brain: beta-amyloid protein and hyper-phosphorylated tau. Both are thought to wreak havoc by causing progressive brain cell death, possibly in part through a process known as oxidative stress.
The brain needs oxygen to function, but using oxygen for energy can produce free radicals; reactive molecules that can damage cells. In a functional brain, free radicals may be removed just as fast as they are produced, preventing them from killing cells. But in Alzheimer’s disease, excessive free radical production may occur faster than it can be removed. Cell death could result.
According to study author Domenico Praticὸ, professor of pharmacology and microbiology and immunology in Temple’s School of Medicine, “Besides the two major signature brain pathologies associated with Alzheimer’s disease, amyloid beta plaques and the tangles which are formed from the phosphorylation of the tau protein, researchers have also known for a while that there is a signature from oxidation stress. But it has always been believed that oxidative stress was just a bystander and did not have an active function in the development of the disease.”
According to a report published in the journal Neurobiology of Aging, Praticὸ and colleagues studied mice that are genetically altered to produce excessive beta-amyloid, called Tg2576 mice. Tg2576 mice also produce an abundance of isoprostane F2α, a molecule that indicates oxidative stress and excessive free radical production. Much prior research had already shown that isoprostane F2α is elevated in people with Alzheimer’s disease.
The scientists found that, when compared to normal mice, the Tg2576 mice had memory problems and increased hyper-phosphorylated tau. They decided to try to block oxidative stress by stopping activity at a brain cell receptor that free radicals are known to bind, the thromboxane receptor. Blocking the thromboxane receptor with a medication reversed the memory problems and accumulation of hyper-phosphorylated tau.
These findings indicate not only that oxidative stress plays a probable role in Alzheimer’s disease, but further suggest that blocking oxidative stress and free radicals via the thromboxane receptor could provide a treatment for Alzheimer’s disease.
Praticὸ stated “For the first time we have identified this receptor as the culprit responsible for the bad things that happen with the disease when high levels of oxygen free radicals are produced.”
The group continues to investigate additional compounds that could block oxidative stress at the thromboxane receptor even more effectively. Further research and eventual human studies are, of course, needed to test whether this approach could help treat Alzheimer’s disease.
The study, “Modulation of AD Neuropathology and Memory Impairments by the Isoprostane F2α Is Mediated by the Thromboxane Receptor,” was published on Oct. 13.
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