NMR provides new clues about how a dipeptide molecule blocks the formation of the toxic amyloid beta-peptide aggregates in the mouse brain. The discovery could put paid to the theory that amyloid beta-peptide causes Alzheimer's disease and suggest a therapeutic lead that focus on the real culprit at an earlier stage.

Alzheimer's disease is an horrendous and debilitating disease not only for sufferers but for the profound impact it can have on family and friends. It is the main cause of age-related dementia and afflicts approximately 15 million people worldwide.

AD is a neurodegenerative disease characterised by tangles of malformed protein, which damage brain cells. However, understanding its origins and whether or not these neurofibrillary plaques and tangles are a symptom of the disease or its underlying cause has remained problematic. As such, although there are drugs and other interventions that can slow the development of cognitive failure and memory problems, there is no cure. As the average age of the population in the developed world rises, AD is set to become one of the biggest problems faced by healthcare systems.

Despite the confusion as to cause and effects, scientists know for certain that even several years before clinical symptoms are manifest, threadlike deposits of incorrectly folded amyloid beta-peptides, known as plaques, form in the brains of Alzheimer's patients. Very recent research has also hinted at evidence that these plaques do not initiate the degeneration of nerve cells but form as a result of this degradation.

Other researchers have discovered that smaller, soluble aggregates of the amyloid-forming peptide seem to be the actual cause of nerve cell damage that ultimately leads to loss of cognitive and memory functions. Indeed, these smaller oligomeric peptides are composed of about twelve peptide units and have been shown to have a strong toxic effect on nerve cells.

Now, Israeli researchers describe a novel approach for the treatment of Alzheimer's disease based on these new insights - a non-toxic molecule that inhibits the formation of these toxic oligomers. Writing in the journal Angewandte Chemie, the team led by Ehud Gazit of the University of Tel Aviv and colleagues there and at the Hebrew University of Jerusalem, describes a new drug molecule comprising two non-physiological amino acids, D-tryptophan and alpha-aminoisobutyric acid. They have demonstrated that this compound improves the cognitive abilities of mice with Alzheimer's disease and reduces the formation of amyloid plaques in their brains.

The team designed its novel drug molecule rationally by coupling the less digestible "D" form of an aromatic amino acid, tryptophane, which contains an indole group, with the non-physiological amino acid, alpha-aminoisobutyric acid, which can act to break protein beta-sheet. Aromatic side-groups are known to play a key role in the aggregation of amyloid-forming peptides, so this portion of the drug molecule can bind to the aromatic core of the amyloid beta-peptide as it forms.

"NMR spectroscopy indicates that the inhibitor interacts with the aromatic core of amyloid-beta," the researchers explain. The other half of the drug then disrupts the folding of the amyloid aggregates into their devastating beta-sheet form.

The small size of the new drug together with its specific chemical properties mean that it is orally active and can be readily absorbed by the digestive tract after ingestion.

The team tested the compound on mice genetically engineered to display all the characteristic symptoms of Alzheimer's disease and found that it normalized the previously disrupted cognitive functions of the rodents. The team also observed a significant decrease in the concentration of amyloid-forming beta-peptides as well as a reduction in the size of the plaques found in the brains of these mice.

Amyloid deposits are associated with several other diseases besides Alzheimer's including Type 2 diabetes mellitus, Parkinson's disease, transmissible spongiform encephalopathies, Huntington's disease, and certain forms of cancer. A clearer understanding of the precursors to the errant peptides and proteins involved in these diseases could ultimately lead to novel drugs for a wide range of disorders.

Related links:

• Angew Chem Int Edn, 2008, 47, 1-7
• Gazit Page

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.