Detangling risk in neurodegenerative disease: Clues to Alzheimer's and beyond

November 2010
Summary Image - Detangling Risk in Neurodegenerative Disease: Clues to Alzheimer’s and Beyond


A Mayo research team is looking one of the less-examined possible causes of Alzheimer’s disease and reporting some interesting findings, which may impact a broader range of neurodegenerative problems.

Leonard Petrucelli, Ph.D.

Leonard Petrucelli, Ph.D.

The potential for diagnosing Alzheimer's disease earlier in life may seem like the ultimate Catch-22. On one hand, why would anybody want to know that they are destined to develop the illness when there is no treatment to prevent its devastating memory loss?

On the other hand, if it is only assessed in patients whose symptoms suggest their brain cells may be damaged beyond repair, how can any new treatment gain traction?

Leonard Petrucelli, Ph.D., chair of neuroscience at Mayo Clinic in Florida, has a definite opinion on the subject. Dr. Petrucelli has spent over a decade studying the spaghetti-like tangles of protein that can form in the brains of Alzheimer's patients with the goal of finding new ways to diagnose the disease and identifying successful treatments.

"The moment you start to show signs or symptoms, these abnormal proteins have already accumulated in the brain to the point that the disease may be unstoppable," says Dr. Petrucelli. "But if you had a good biomarker that could be used to predict who is going to get Alzheimer's, you could start therapy sooner. Right now we don't know if clinical trials for Alzheimer's disease have failed because the drug didn't work or because we started too late."

Team Tau: The Road Less Traveled

Mouse brain cells

Brain cells (cell nuclei labeled blue) generated from mouse pups were made to express a human protein (tau) implicated in neurodegenerative disease. As shown in the figure, human tau expression (green) is detected in mouse neurons (red). Scale bar=20 microns

Petrucelli has long been fascinated with neurological disorders such as Alzheimer's disease, frontotemporal lobar dementia, Parkinson's disease and amyotrophic lateral sclerosis (ALS). He says the common thread that runs through all of these illnesses is the abnormal accumulation of one protein or another. In Alzheimer's disease, two such culprits have emerged: amyloid beta and tau.

The bulk of research efforts have been focused on the short peptides of amyloid beta that can aggregate and form areas of plaque on the brain. But an equal, and perhaps underappreciated, partner in the demise of Alzheimer's brain cells is the tau protein, which when damaged can assemble into so-called neurofibrillary tangles. Dr. Petrucelli is on Team Tau.

"Only recently has sufficient momentum been generated to look at tau as a legitimate target for the treatment of Alzheimer's disease," says Dr. Petrucelli. "The majority of clinical trials in the pipeline are focused on amyloid beta, but the role of tau cannot be ignored; the more tau you have, the more memory impairment you have. So we are going to need to attack the disease from both directions in order to successfully treat Alzheimer's disease."

Normally, tau regulates the dynamics of microtubules, structures critically important for both maintaining cellular architecture as well as transporting materials inside the cell. When mutations arise, the tau protein can no longer do its job and gets tagged as "trash" through a process called hyperphosphorylation. The tagged tau proteins are prone to aggregation and accumulate into "mini-trash dumps" within the brain, polluting the atmosphere so that normal cells start to die off.

Dr. Petrucelli has recapitulated this disease process in the laboratory: first in cultured neuronal cells and then in mice, which have been genetically engineered to develop the same fibrous tangles and cognitive decline seen in humans. Using these experimental models, he has identified a number of proteins and key pathways that can be exploited to clear out the tau "junkyard." Many of these proteins are known as chaperones because they can spot proteins gone awry and escort them out of the cell or target them for degradation.

He has just launched a major drug discovery program to identify and test molecular chaperones. His laboratory is screening a chemical library of 50,000 compounds with the hope that one or more can reverse the neurodegenerative effect of tangles in cells, then in mice, and, ultimately, in humans. What Dr. Petrucelli is looking for is a new drug to treat illnesses marked by abnormal tau, such as Alzheimer's disease and another form of dementia called frontotemporal lobar degeneration (FTD).

Hope Renewed

Mouse's hippocampus region.

Mouse pups were injected in the brain with a neurotoxic fragment of TDP-43 (TDP25), which was tagged with green-fluorescent protein. Expression of TDP25 was evaluated when mice were 1 month old, and aggregates were detected in the hippocampus, a brain region involved in learning and memory. Mouse neurons were labeled red, and cell nuclei were labeled blue.

Mouse brain cells.

Brain cells (cell nuclei labeled blue) generated from mouse pups were made to express green fluorescent protein, and stained for a protein recently implicated in neurodegeneration, known as TDP-43 (red). Scale bar=10 microns

In a circuitous round of events, studies on Alzheimer's disease have led to discoveries in FTD — the most common form of dementia in people over the age of 65. Even though the brain cells of all patients with FTD exhibit tangles, only half of them show mutations in tau. In 2006, researchers discovered the cause of this discrepancy: TDP-43, another abnormal protein.

The discovery has since led to a breakthrough in another devastating neurological condition, ALS or Lou Gehrig's disease. A number of researchers, including Dr. Petrucelli and colleagues at Mayo, identified mutations in TDP-43 in both familial and sporadic cases of ALS. The finding provided a molecular link between cases that ran in families and those that appeared sporadically in the population.

"It has completely rejuvenated the field," says Dr. Petrucellli. "All the models researchers had been focusing on for the last 15 years — cell cultures, worm models, mouse models — they were all based on mutations in a gene called SOD1, which was implicated only in familial ALS. So whenever they discovered a drug that worked well in these models and then later tried to do clinical trials for ALS in what were then largely sporadic cases, the drug ultimately failed. Now with TDP-43, we can generate models that should be more valuable for drug discovery because they are relevant to all forms of the illness. So we are no longer positioning ourselves to fail."

Dr. Petrucelli's laboratory has already mutated TDP-43 in a number of cell culture models and several lines of transgenic mice, all of which can be used both to understand the mechanism of disease and to search for drug treatments. His work has taken him from one neurodegenerative disorder to another ... and back again.

Half of Alzheimer's disease cases have faulty TDP-43; even though all of them have plaques and tangles, the underlying molecular basis for those defects can be different from case to case — differences that may greatly affect the success of a new treatment. Unfortunately, they can only be distinguished at autopsy, by experts like Mayo's renowned neuropathologist Dennis Dickson, M.D.

Hope lies in the prospect of, the protein also accumulating in a more accessible spot than the brain, such as the cerebrospinal fluid that circulates around the brain and spinal cord. If that is the case, it could become a valuable biomarker of Alzheimer's disease or ALS and enable physicians to diagnose the disease earlier when new therapies may be able to halt it in its tracks. Dr. Petrucelli is investigating this line of thought with Mayo neurologist Kevin Boyland, M.D., by tracking the levels of TDP-43 protein in bodily fluids from patients with ALS.

"I think there is renewed hope now that we recognize TDP-43 as the major pathological hallmark of ALS," Dr. Petrucelli says. "We can truly begin the work of testing new ways to combat the disease."