Possible Missing Link in Alzheimer’s Pathology Identified -BB

Alzheimer’s disease has long been characterized by the buildup of two distinct proteins in the brain: first beta-amyloid, which accumulates in clumps, or plaques, and then tau, which forms toxic tangles that lead to cell death. But how beta-amyloid leads to the devastation of tau has never been precisely clear. Now a new study at the University of Alabama at Birmingham appears to describe that missing mechanism.

The study details a cascade of events. Buildup of beta-amyloid activates a receptor that responds to a brain chemical called norepinephrine, which is commonly known for mobilizing the brain and body for action. Activation of this receptor by both beta-amyloid and norepinephrine boosts the activity of an enzyme that activates tau and increases the vulnerability of brain cells to it, according to the study, published in Science Translational Medicine.

Essentially, beta-amyloid hijacks the norepinephrine pathway to trigger a toxic buildup of tau, says Qin Wang, the study’s senior author and a professor of neuropharmacology in the department of cell, developmental and integrative biology at the University of Alabama at Birmingham. “We really show that this norepinephrine is a missing piece of this whole Alzheimer’s disease puzzle,” she says.

This cascade explains why so many previous Alzheimer’s treatments have failed, Wang says. Most of the drugs developed in recent decades have targeted the elimination of beta-amyloid. But the new research suggests that norepinephrine amplifies the damage wrought by that protein.

Beta-amyloid itself can kill neurons but only in very high doses, Wang says. Add norepinephrine, and it takes only 1 to 2 percent as much beta-amyloid to eliminate brain cells in a lab dish. So with treatments that targeted beta-amyloid but left the norepinephrine pathway intact, there was enough beta-amyloid remaining to do significant damage, she says. But if the norepinephrine pathway really is crucial to the development of Alzheimer’s, it suggests new ways to treat the disease, which currently afflicts 5.8 million Americans.

A drug that was developed to treat depression but too ineffective to win approval seems to act on this same pathway, Wang says. The drug, idazoxan, which has also been studied in schizophrenia, has already passed through initial clinical testing and been shown to be safe, she adds.

Wang is now looking to promote larger clinical trials of idazoxan to see if it can be used to effectively treat early-stage Alzheimer’s. She hopes that eventually, a drug can be developed that will act on this Alzheimer’s-related pathway in a more targeted way to minimize side effects and maximize effectiveness.

Stephen Salloway, a professor of psychiatry and neurology at the Warren Alpert Medical School at Brown University, who was not involved in the new research, says he doesn’t think Alzheimer’s will yield so easily to a new drug targeting the norepinephrine pathway. “I doubt there’s something simple that’s going to come out of this,” says Salloway, who is also director of neurology and the Memory and Aging Program at Butler Hospital in Providence, R.I. “I’d be shocked if it works.”

Such a drug might, however, be part of a “therapeutic package” of treatments that could eventually make headway against Alzheimer’s, he says. “The goal is to get a biological foothold and then build on it,” he adds. “The more targets we have, the bigger the impact.”

Eric Reiman, CEO of Banner Alzheimer’s Institute, an Arizona-based research and advocacy group, agrees that the study suggests new possibilities for treatment. “It provides a mechanism that could be targeted by investigational and, potentially, repurposed drugs,” he says. “And it offers hypotheses that can now be tested and extended by the field.” Salloway, Reiman and other experts emphasize that the findings are preliminary and need to be confirmed by future research.

Wang has long studied norepinephrine because of its role in thinking and complex behaviors. She stumbled across the connection to Alzheimer’s as part of that research, she says.

In two strains of mice and in human tissue in their new study, she and her colleagues showed that small pieces of beta-amyloid bind to a receptor for norepinephrine, activating the GSK3-beta enzyme and triggering the tau to become toxic. They confirmed this relationship by blocking the receptor with idazoxan in two strains of middle-aged mice for eight weeks. Doing so deactivated the enzyme and prevented the tau from becoming toxic.

For years, researchers had wondered how beta-amyloid and tau were connected, says Rudolph Tanzi, an expert on the molecular genetics of Alzheimer’s disease at Massachusetts General Hospital, who was not involved in the new research. Scientists essentially assumed that beta-amyloid caused tau tangles through a complicated chain of events, he says.

Then, in a 2014 paper in Nature, Tanzi and his colleagues used human brain cells grown in a dish to reveal a problem with the theory: mice—the main source of research information on Alzheimer’s—do not have the right form of tau to cause tangles in people. Instead the researchers showed that in the human cells, beta-amyloid led directly to tau tangles. Tanzi and his colleagues blocked a variety of different enzymes called kinases to try to stop the process. They found two, both of which blocked the GSK3-beta enzyme—the same one that Wang and her colleagues identified in their Science Translational Medicine paper.

The new study, Tanzi says, takes his own work a step further by showing how beta-amyloid triggers activation of the toxic tau. “It’s an important paper,” he adds. “If it’s replicated, it provides a good drug target.”

Tanzi believes that inflammation is a key player in Alzheimer’s, triggering the cascade that leads to disease. He has previously described beta-amyloid as the match and tau tangles as the brush fires burning in the brains of people with the disease. “GSK3-beta, I guess you could say, is the kindling for the brush fire. And this explains how the match gains access to the kindling,” Tanzi says. Once the neuroinflammation starts, brain cells die at a far faster rate, he adds.

Tanzi says he has unpublished data on dozens of drugs that stop beta-amyloid from triggering taut tangles, many of which support what Wang and her colleagues found in their new paper. “I believe their data is going to hold up,” he says. “And it’s exciting.”

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