Study reveals potential new strategy to prevent Alzheimer's disease

October 7, 2016 by Graciela Gutierrez
Diagram of the brain of a person with Alzheimer's Disease. Credit: Wikipedia/public domain.

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.

Credit: Baylor College of Medicine

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 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 ," 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 – , 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 .

"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 , 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.

Explore further: Abnormal brain protein may contribute to Alzheimer's disease development

More information: Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model, Neuron, Available online 6 October 2016, ISSN 0896-6273, dx.doi.org/10.1016/j.neuron.2016.09.022.

Related Stories

Abnormal brain protein may contribute to Alzheimer's disease development

September 30, 2016
A recently-recognized pathologic protein in the brain may play a larger role in the development of clinical Alzheimer's disease dementia than previously recognized, according to a study by researchers at Rush University Medical ...

Memory loss not enough to diagnose Alzheimer's

September 13, 2016
Relying on clinical symptoms of memory loss to diagnose Alzheimer's disease may miss other forms of dementia caused by Alzheimer's that don't initially affect memory, reports a new Northwestern Medicine study.

New imaging technique in Alzheimer's disease opens up possibilities for drug development

September 28, 2016
Tau PET is a new and promising imaging method for Alzheimer's disease. A case study from Lund University in Sweden now confirms that tau PET images correspond to a higher degree to actual changes in the brain. According to ...

'Pac-Man' gene implicated in Alzheimer's disease

July 26, 2016
A gene that protects the brain from the harmful build-up of amyloid-beta, one of the causative proteins implicated in Alzheimer's disease, has been identified as a new target for therapy by NeuRA researchers.

Dementia plaques attack language center of brain

March 7, 2016
The recent ability to peer into the brain of living individuals with a rare type of language dementia, primary progressive aphasia (PPA), provides important new insights into the beginning stages of this disease—which results ...

Genetically engineered mice suggest new model for how Alzheimer's causes dementia

July 4, 2016
Using a novel, newly developed mouse model that mimics the development of Alzheimer's disease in humans, Johns Hopkins researchers say they have been able to determine that a one-two punch of major biological "insults" must ...

Recommended for you

Thinking 'out-of-the-box' may build a better brain and prevent dementia

September 25, 2017
More than 5 million Americans today are affected by Alzheimer's disease (AD). If nothing is done to stop this upward trajectory, there will be more than 16 million people with AD in the United States and more than 60 million ...

Multi-gene test predicts Alzheimer's better than APOE E4 alone

September 22, 2017
A new test that combines the effects of more than two dozen genetic variants, most associated by themselves with only a small risk of Alzheimer's disease, does a better job of predicting which cognitively normal older adults ...

Personality changes don't precede clinical onset of Alzheimer's, study shows

September 21, 2017
For years, scientists and physicians have been debating whether personality and behavior changes might appear prior to the onset of Alzheimer's disease and related dementias.

Newly ID'd role of major Alzheimer's gene suggests possible therapeutic target

September 20, 2017
Nearly a quarter century ago, a genetic variant known as ApoE4 was identified as a major risk factor for Alzheimer's disease—one that increases a person's chances of developing the neurodegenerative disease by up to 12 ...

Is the Alzheimer's gene the ring leader or the sidekick?

September 15, 2017
The notorious genetic marker of Alzheimer's disease and other forms of dementia, ApoE4, may not be a lone wolf.

Potential noninvasive test for Alzheimer's disease

September 6, 2017
In the largest and most conclusive study of its kind, researchers have analysed blood samples to create a novel and non-invasive way of helping to diagnose Alzheimer's disease and distinguishing between different types of ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.