Common diseases like Parkinson's, Alzheimer's and dementia are
caused in part by abnormal accumulation of certain proteins in the
brain. Taking a pill that prevents the accumulation of toxic molecules in
the brain might someday help prevent or delay Alzheimer's disease, revealed scientists at Baylor College of Medicine, Texas Children's
Hospital and Johns Hopkins University School of Medicine.
The study, published in Cell Press journal Neuron
took a three-pronged approach to help subdue early events that occur in
the brain long before symptoms of Alzheimer's disease are evident. The
scientists were able to prevent those early events and the subsequent
development of brain pathology in experimental animal models in the lab.
‘Inhibition of the Nuak1 enzyme consistently resulted in lower levels of tau protein. In the future it might be possible to treat people at risk for Alzheimer's disease by keeping tau low.’
Senior author Dr. Huda Zoghbi, professor of molecular and
human genetics and of pediatrics - neurology and developmental
neuroscience at Baylor and director of the Jan and Dan Duncan
Neurological Research Institute at Texas Children's Hospital, said, "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."
"Scientists in the field have been focusing mostly on the final
stages of Alzheimer's disease," said first author Dr. Cristian
Lasagna-Reeves, postdoctoral fellow in the Zoghbi lab. "Here 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."
The 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.
Cells control the amount of their proteins with other proteins
called enzymes. 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,
who is also an investigator at the Howard Hughes Medical Institute.
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.
"Screening hundreds of kinases in the fruit fly animal model was
critical because we could assess degeneration caused by tau in the fly's
nervous system and measure neuronal dysfunction. Screening such a large
number cannot be done with other animal models like the mouse, and
cultured cells cannot model complex nervous system functions," said
co-senior author Dr. Juan Botas, professor of molecular and human
genetics and of molecular and cellular biology at Baylor.
Brain section from mouse carrying the dementia-causing P301S mutation
in human tau shows accumulation of tau neurofibrillary tangles (in dark
brown, left). When Nuak1 levels are decreased by 50% (P301S/Nuak1+/-;
right), 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 behavior of the mice and prevented brain
"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 next step is to
develop drugs that will inhibit Nuak1 in hope that one day would be
able to lower tau levels with low toxicity in individuals at risk for
dementia due to tau accumulation."
Scientific studies like this one that uncover basic biological
mechanisms of disease make it possible to develop new strategies to
prevent or treat diseases such as Alzheimer's, Parkinson's or dementia.
In the future it might be possible to treat people at risk for
Alzheimer's disease by keeping tau low. Think of how taking drugs that
lower cholesterol has helped control the accumulation of cholesterol in
blood vessels that leads to atherosclerosis and heart disease.
"When people started taking drugs that lower cholesterol, they
lived longer and healthier lives rather than dying earlier of heart
disease," said Zoghbi. "Nobody has thought about Alzheimer's disease in
that light. Tau in Alzheimer's can be compared to cholesterol in heart
disease. Tau is a protein that when it accumulates as the person ages,
increases the vulnerability of the brain to developing Alzheimer's. So
maybe if we can find drugs that can keep tau at levels that are not
toxic for the brain, then we would be able to prevent or delay the
development of Alzheimer's and other diseases caused in part by toxic