Study Reveals Potential New
Strategy
to Prevent Alzheimer’s Disease
By Graciela Guitierrez,Baylor School
of Medicine
to Prevent Alzheimer’s Disease
By Graciela Guitierrez,
Houston, TX - Oct 6, 2016 -- Taking
a pill that prevents the accumulation of toxic molecules in the brain might
someday help prevent or delay Alzheimer’s disease, according to scientists at
Baylor College of Medicine, Texas Children’s Hospital and Johns Hopkins
University School of Medicine.
The study, published
today 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.
“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 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. “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.
“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
degeneration.”
“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 tau
accumulation.”
“Just like people now
take their cholesterol-lowering medications, people in the future could be
taking medications to keep tau levels low and prevent the development of
Alzheimer’s disease,” said Lasagna-Reeves.
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