Friday, February 8, 2019

“A new culprit has emerged in the quest to understand how Alzheimer’s attacks the human brain”




“A team of scientists at the Fisher Center for Alzheimer’s Research laboratory at Rockefeller University managed to isolate a metabolite called C99 and found — quite unexpectedly — that it seems to cluster in regions of the brain that are most susceptible to Alzheimer’s.
“‘It was a total surprise because we saw the places where C99 accumulates in the brain of Alzheimer’s patients are exactly the places where neurons later are going to die,’ says Victor Bustos, senior research associate at the Fisher Center for Alzheimer’s Research. ‘C99 becomes a very good marker for neurodegeneration.

“In the world of dementia research, having a new ‘marker’ is important because these are the targets scientists go after when they test drugs in the hopes of finding a cure for Alzheimer’s. So far, that cure has been elusive, and this discovery suggest a possible reason why. Perhaps researchers have been aiming at the wrong target.

“The markers most associated with Alzheimer’s are the so-called ‘plaques’ and ‘tangles’ that accumulate in the brain of people with this disease. The plaques are clumps of beta-amyloid protein that coat neurons as the disease advances, and the tangles are tau proteins that go awry inside the neurons.

“Alzheimer’s research has focused heavily on medicines that seek to clear way amyloid plaque, but those efforts have led to a long string of disappointing results. Even when the drugs have reduced plaque, the memory of Alzheimer’s patients has not improved. Bustos says some regions of the brain are heavily affected by Alzheimer’s, while other regions aren’t. For someone suffering from the disease, beta-amyloid is present in high amounts in both regions, he says. ‘So that is kind of an argument to say beta-amyloid may not be well-enough related to Alzheimer’s disease to be the cause of Alzheimer’s,’ Bustos says.

“What he and his colleagues did was go in search of other potential culprits, using a technique that includes sophisticated super-resolution microscopy. ‘We decided to look at C99 because it is the precursor of beta-amyloid,’ Bustos says. ‘Before beta-amyloid becomes beta-amyloid, it is first called C99. You can call it an intermediate in the production of amyloid.’

“Bustos and his colleagues knew they had found something important when C99 showed up in high concentrations in areas of the brain most involved in memory, but not in other areas of the brain less susceptible to Alzheimer’s. ‘The hippocampus is one of the first areas to degenerate in Alzheimer’s disease, and we observed an early accumulation of C99 in the hippocampus,’ he says. ‘Later, after the hippocampus has degenerated, the frontal cortex starts to degenerate. We observed the same pattern. There was a secondary accumulation of C99 in the frontal cortex. Those are areas that are vulnerable to Alzheimer’s.’

“The significance of this result led the research team to post its findings online, rather than wait out the lengthy process of getting it published in a peer-review journal. ‘That way, people can know about these findings,’ Bustos says. ‘We have had an extraordinary response. In less than a week after it was public, I could see that already 3,600 people had looked at the paper, which is an extraordinary number.’

“Dr. Michelle Papka, founder and director of the Cognitive and Research Center of New Jersey, has read the paper and describes it as ‘a very interesting finding and a very worthwhile hypothesis to pursue.’ Papka was not involved in this study, but has been treating people with Alzheimer’s and engaging in dementia research for more than two decades. She describes the finding just published as a ‘pilot study, a preliminary first step.’

“If further research were to confirm that C99, not amyloid, is a primary driver of neurological damage in Alzheimer’s patients, that could open new avenues of research that might bring better results. ‘If it turns out this is correct, some of these anti-beta preventions may have been going after the wrong targets, and that may be why some have led to futile results,’ Papka says. ‘This type of research might help us determine more specifically what we need to target.’

“Based on his research, Bustos is not suggesting that amyloid is the wrong target. ‘I believe both C99 and amyloid contribute to the disease because amyloid is a toxic substance,’ he says. However, he says past efforts may have been flawed because many of the medicines used to attack beta-amyloid in clinical trials have done so in a way that actually raises the level of C99 in the brain.

“‘We believe C99 is the most toxic substance, so what we propose is that instead of reducing amyloid and increasing C99, we should aim at strategies that decrease both C99 and amyloid,’ he says. ‘What this study is telling the pharmaceutical companies is, please focus your resources on lowering C99; it’s a much better target than amyloid alone.’”


The Fisher Center lab at Rockefeller University is a leading scientific center focusing on Alzheimer’s disease. The research involving C99 was funded by the Fisher Center for Alzheimer’s Research Foundation, whose mission is to understand the causes of Alzheimer’s, improve the care of those living with it and find a cure. For more information, visit the foundation’s website at www.alzinfo.org



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