Neurodegenerative conditions

Neurodegenerative conditions

ScienceDaily (June 13, 2008) — Queensland Brain Institute (QBI) neuroscientists at UQ have discovered a new way to reduce neuronal loss in the brain of a person with Alzheimer's disease.

Memory loss in people with Alzheimer's disease can be attributed to several factors. These include a build-up of the neuro-toxin Amyloid beta -- the major component of amyloid plaques found in patients with Alzheimer's -- and corresponding degeneration of a specific population of nerve cells in the basal forebrain.

Dr Elizabeth Coulson, QBI neuroscientist, said the research had established that the molecule known as p75 neurotrophin receptor was necessary for the Amyloid beta to cause nerve cell degeneration in the basal forebrain.

During her research, Dr Coulson's team found -- both in cultured cells and in an animal model of Alzheimer's disease -- that it was possible to completely prevent Amyloid beta toxicity by removing the p75 cell death receptor.

"Discovering how Amyloid beta triggers neuronal degeneration has been a question bugging neuroscientists for decades, and we have identified an important piece of the puzzle," Dr Coulson said.

These results provide a novel mechanism to explain the early and characteristic loss of brain cells that occurs in Alzheimer's disease -- which are known to be important for memory formation.

Dr Coulson already has patented molecules that can block p75 and is ready to begin testing them in animal models of Alzheimer's disease.

"If such therapy is successful, it probably wouldn't cure this multifaceted disease," Dr Coulson said.

"But it would be a significant improvement on what is currently available for Alzheimer's disease patients."

The World Health Organisation predicts that by 2040, neurodegenerative conditions will become the world's leading cause of death, overtaking cancer.

Alzheimer's disease is the most common dementia affecting 10 per cent of people over 65 and 40 per cent over 80 years of age.

Significant advances in determining the molecular regulation of nerve cell function and survival have major impact on our understanding of more complex areas such as behaviour, cognition, aging and neurological diseases.

Abnormal accumulation of amyloid fibers and other misfolded forms in the brain cause neurodegenerative diseases. Similarly, build-up of abnormally folded prion proteins between neurons causes the human version of mad cow disease, Creutzfeldt-Jakob disease.

"Surprisingly, a small molecule called DAPH selectively targets the areas that hold fibers together, and converts fibers to a form that is unable to grow. Normally fibers grow from their ends, but the drug stops this activity," says senior author James Shorter, PhD, Assistant Professor of Biochemistry and Biophysics. "Our data suggest that it is possible to generate effective small molecules that can attack amyloid fibers, which are associated with so many devastating diseases."

The researchers are now working on how DAPH acts as a wedge to stop the fibers from growing. "Presumably DAPH fits very neatly into the crevices between fiber subunits," explains Shorter. "When we grow yeast cells with the prion in the presence of DAPH, they begin to lose the prion. We also saw this in the test tube using pure fibers. The small molecule directly remodels fiber architecture. We've really been able to get at the mechanism by which DAPH, or any small molecule, works for the first time." DAPH was originally found in a screen of small molecules that reduce amyloid-beta toxicity in the lab of co-author Vernon Ingram, Shorter's collaborator at the Massachusetts Institute of Technology (MIT).

In a test tube, if a small amount of amyloid or prion fiber is added to the normal form of the protein, it converts it to the fiber form. But when DPAH is added to the mix, the yeast prion protein does not aggregate into fibers. "It's essentially stopping fiber formation in its tracks," says Huan Wang, first author and research specialist in Shorter's lab. "We were surprised to see two very different proteins, amyloid-beta and Sup35, sensitive to this same small molecule."

The next step is to identify more potent DAPH variants with greater selectivity for deleterious amyloids. Since some amyloids may turn out to be beneficial -- for example, one form may be involved in long-term memory formation -- it will be necessary to find a drug that does not hit all amyloids indiscriminately. "We'd need one that hits only problem amyloids, and DAPH gives us a hint that such selectivity is possible" says Shorter.

This work was initiated in Susan Lindquist's lab at MIT and completed at Penn. The study was funded by the National Institute of General Medical Sciences, the Alzheimer's Association, the Kurt and Johanna Immerwahr Fund for Alzheimer Research, a DuPont-MIT alliance, the American Heart Association, and pilot grants from the University of Pennsylvania Alzheimer's Disease Core Center and Institute on Aging.