Taking a pill that stops the accumulation of toxic molecules in the brain may help prevent or delay Alzheimer’s disease, according to a new study. Scientists at Baylor College of Medicine, Texas Children’s Hospital and Johns Hopkins University School of Medicine in the US took a three-pronged approach to help subdue early events that occur in the brain long before symptoms of Alzheimer’s disease are evident.
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They were able to prevent those early events and the subsequent development of brain pathology in experimental animal models in the lab. “Common diseases like Parkinson’s, Alzheimer’s and dementia are caused in part by abnormal accumulation of certain proteins in the brain,” said senior author Huda Zoghbi.
“Some proteins become toxic when they accumulate; they make the brain vulnerable to degeneration. Tau is one of those proteins involved in Alzheimer’s disease and dementia,” Zoghbi said.
“We tried to find clues about what is happening at the very early stages of the illness, before clinical irreversible symptoms appear, with the intention of preventing or reducing those early events that lead to devastating changes in the brain decades later,” said first author Cristian Lasagna-Reeves, postdoctoral fellow in the Zoghbi lab.
Scientists reasoned that if they could find ways to prevent or reduce tau accumulation in the brain, they would uncover new possibilities for developing drug treatments for these diseases.
To find which enzymes affect tau accumulation, the scientists systematically inhibited enzymes called kinases.
“We inhibited about 600 kinases one by one and found one, called Nuak1, whose inhibition resulted in reduced levels of tau,” said Zoghbi.
The scientists screened the enzymes in two different systems, cultured human cells and the laboratory fruit fly.
Screening in the fruit fly allowed the scientists to assess the effects of inhibiting the enzymes in a functional nervous system in a living organism.
Brain section from mouse carrying the dementia-causing P301S mutation in human tau shows accumulation of tau neurofibrillary tangles. When Nuak1 levels are decreased by 50 per cent, fewer tau tangles accumulate.
“We found one enzyme, Nuak1, whose inhibition consistently resulted in lower levels of tau in both human cells and fruit flies,” said Zoghbi.
“Then we took this result to a mouse model of Alzheimer’s disease and hoped that the results would hold, and they did. Inhibiting Nuak1 improved the behaviour of the mice and prevented brain degeneration,” he said.
“Confirming in three independent systems – human cells, the fruit fly and the mouse – that Nuak1 inhibition results in reduced levels of tau and prevents brain abnormalities induced by tau accumulation, has convinced us that Nuak1 is a reliable potential target for drugs to prevent diseases such as Alzheimer’s,” said Zoghbi.
The study was published in the journal Neuron.
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