Team Hutton

Within the higher functioning portions of the brain of a person with Alzheimer's disease, twisting threads made up of chains of tiny "tau" proteins assemble inside billions of nerve cells (neurons). Outside the neurons, other amyloid-beta (Αβ) proteins fuse to form sticky clumps called plaque - akin to the substance that clogs heart arteries. Together, these tangles and plaques disrupt the normal functioning of the nerve cells, destroying the pathways along which packets of information move. Fewer neurons are then available to store and retrieve memory.

Estimates released in March, 2007, show that the incidence of Alzheimer's disease is rising rapidly. According to the Alzheimer's Association, more that 5 million people have the disease— a number they expect will triple by 2050. While most people afflicted are older that 65, as many as 500,000 people younger than 65 have some form of early onset dementia. Dementia-related Medicare costs are expected to double, to $189 billion, by 2015.

Mayo Clinic's Alzheimer's Disease Research Center

The Alzheimer's Disease Research Center is one of 30 centers across the country designated and funded by the National Institute on Aging of the National Institutes of Health. The center provides care for dementia patients and promote research and education on Alzheimer's disease and related dementias. Mayo Clinic's ADRC is jointly based in Rochester, Minn., and Jacksonville, Fla., where Dr. Hutton's lab is located.

Genetically Engineering Mouse Models

Dr. Hutton's group was the first to genetically engineer a mouse that expresses a mutation of the gene which controls tau production. In a paper published in Nature Genetics, the team reported that the mouse develops the same kind of neurofibrillary tangles seen in human dementia ( Nature Genetics 25, 402 – 405; 01 Aug 2000). The work provided scientists with a key research tool — a small lab animal that closely approximates the pathology of Alzheimer's disease in humans. The following year, in the journal Science, the team presented the first mouse to exhibit tangles and plaques, key characteristics of Alzheimer's disease. The transgenic mouse offered researchers the best animal model possible to test therapies aimed at slowing down, or halting, neurodegeneration ( Science 2001 Aug 24;293(5534):1487-91). It also strengthened the notion that tangle development followed plaque development.

"These mice produced more tangles than those with only a tau mutation," says Dr. Hutton. "That means there must be interaction between tau and amyloid that is causing cognitive deficits."

But how does tau interact with amyloid-beta?— that's the next million dollar question.

The Relationship Between Tau and Amyloid-Beta

Tau helps stabilize the road-like microtubules that run inside nerve cell bodies. And in the world of neurobiology, tau is the big player, responsible for about 30 forms of neurodegeneration, including fronto-temporal dementia, the second most common form of dementia after Alzheimer's. In contrast, Alzheimer's disease is the only form of dementia in which amyloid-beta is involved.

As Alzheimer's develops, the shape of tau molecules inside neurons changes; the molecules begin to fall off the microtubules they once supported, and bind to form paired and twisted filaments. The process is toxic to the microtubules, which can no longer transport the molecular cargo needed to keep the neuron alive.

"We think amyloid-beta stresses neurons, releasing cascades of signals that cause the tau to be released," explains Dr. Hutton. "Then, either the microtubule pathways break down because of loss of tau, or they are blocked by tau tangles — we don't yet know which process kills the neuron."

Because of the connection between amyloid-beta and tau loss, the researchers believe that progression of the disease could be prevented if amyloid-beta is treated before the onset of tau damage.

Restoring Memory Via Tau

From left to right: Michael Hutton, Ph.D., Dennis Dickson, M.D., and Jada Lewis, Ph.D.

The tau transgenic mice feature a unique "switch" - to turn the expression of the mutant gene on or off so that the disease at both early and late stages. In experiments with the mice, Dr. Hutton, Jada Lewis, Ph.D., and their collaborators at the University of Minnesota were stunned to find that they were able to reverse tau pathology early on, and to restore memory to mice that had started to develop cognitive problems.

But they were in for an even bigger surprise.

"What was absolutely staggering is that we aged the mice to the point where many neurons had died," recounts Dr. Hutton. "They couldn't remember any of their tasks but, when we hit this molecular switch, they recovered a lot of their memory."

To the research team, this demonstrated that Alzheimer's disease is potentially a reversible process. Once you get the disease, the effectiveness of amyloid-beta therapy may be limited. The discovery pointed to tau as a potentially exciting target for new therapies because it showed it may still be possible to halt tau degradation and restore damaged nerves. Their achievement was reported in 2005 in Science (2005 Jul 15;309(5733):476-81).

"The studies suggest that toxicity to neurons caused by tau begins before tangles develop," says Dr. Lewis, a co-developer of the mouse model. "If that's true, we may be able to repair that process so that the neuron can rebound."

The findings not only changed the scientists' ideas about the potential for recovery in Alzheimer's, but also about the cause of memory loss in the first place.

In ongoing studies, the researchers are using the tau mouse to test small molecules — ones that have already been developed for other diseases, such as cancer — that may stop tau from initially changing its chemical shape. One design for a therapeutic drug could be to inhibit the molecules involved in the abnormal phosphorylation (the addition of a phosphate group) of tau, and another might be to find a way to stabilize the microtubules.

Tau's Next Door Neighbor: A New Discovery

In yet another notable achievement, Dr. Hutton led a group of collaborators within Mayo Clinic, the University of British Columbia and Vancouver Coastal Health Research Institute in Vancouver, Canada, and the University of Manchester in the United Kingdom who discovered that mutations in the progranulin gene cause frontotemporal dementia (FTD) — a group of brain disorders that affect the frontal and temporal lobes of the brain, which control personality and speech ( Nature 2006 Aug 24;442(7105):916-9).

View a video about this discovery (from the news release at http://www.mayoclinic.org/news2006-jax/3537.html)

Progranulin (PGRN) is a type of protein known as a growth factor. The gene that codes for progranulin was not an obvious one to sequence in the hunt for mutations that cause neurodegenerative disease. The lab analyzed over 80 genes close to the tau gene in both healthy people and those with FTD. It was not until they sequenced the progranulin gene, located in the same genetic region, that they found the first disease-causing mutation.

The researchers solved a ten-year genetic puzzle to explain a large number of FTD cases in North America and Europe. Their research indicates that progranulin function plays an important but previously unrecognized role in the survival of nerve cells.

"Other neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and even FTD caused by mutations in the tau gene, are characterized by the accumulation of disease-specific proteins within surviving brain cells," says Dr. Hutton. "What we've found is a little bit different— it's simply the loss of progranulin that's causing the disease."

The discovery also implies hope for other brain disorders, such as Lou Gehrig's disease (amyotrophic lateral sclerosis) in which the loss of certain growth factor-type proteins can actually give rise to the disease. With discovery of the mechanism that causes the disease behind them, the next step is to develop new treatments.

"It might be possible to replace progranulin through gene therapy," says Dr. Hutton. "Or perhaps progranulin production could be increased from the surviving copy of the gene."

Dr. Hutton's lab has begun to investigate whether normal variability in the progranulin gene influences the risk of developing Alzheimer's disease or Parkinson's disease.

Like all basic scientists at Mayo Clinic, Dr. Hutton asks a clinical question:

"If you have a particular, common, variant in the progranulin gene, are your neurons better able to withstand the kind of damage they get from accumulation of amyloid beta?" And does that mean those patients are protected from getting Alzheimer's disease or at a lower risk?"

Dr. Hutton has received both the MetLife Award, and the Potamkin Prize— the most prestigious awards made to senior scientists working in the neuroscience research field. In 2006, he was named a Mayo Clinic Distinguished Investigator. With those credentials and his track record of success, we can anticipate dogged pursuit until he has answered his own question.