Angewandte Chemie International Edition ,
Hope for Alzheimer’s Patients?
Dipeptide blocks the formation of toxic amyloid β-peptide aggregates in mice
Contact: Ehud Gazit, Tel Aviv University (Israel)
Registered journalists may download the original article here:
Cognitive-Performance Recovery of Alzheimer's Disease Model Mice by Modulation of Early Soluble Amyloidal Assemblies
disease is the primary cause of age-related dementia. About 15 million
people are affected by this neurodegenerative disease worldwide. It has
so far not been possible to combat the causes of Alzheimer’s disease.
Israeli researchers have now developed a novel approach for treatment.
As they report in the journal Angewandte Chemie, the new drug, a
molecule made from two nonphysiological amino acids, improves the
cognitive abilities of mice with Alzheimer’s and reduces the amyloid
plaques in their brains.
years before clinical symptoms appear, threadlike deposits of
incorrectly folded amyloid β-peptides,
known as plaques, form in the brains of Alzheimer’s patients. It was
previously assumed that these plaques initiate the degeneration of nerve
cells; however, more recent discoveries indicate that smaller, soluble
aggregates of the amyloid-forming peptide are the actual cause for the
loss of learning and memory functions. These oligomers of about twelve
peptide units have a strong toxic effect on nerve cells. The new
therapeutic approach taken by researchers working with Ehud Gazit at the
University of Tel Aviv aims to block the formation of these toxic
drug molecule was rationally designed that contains an aromatic amino acid
and a β-sheet
breaker. Aromatic side-groups play a key role in the
aggregation of amyloid-forming peptides; the drug should thus bind to
the aromatic core of the β-amyloid
peptide through its aromatic element. Also, in amyloid aggregates, the
proteins adopt the form of β-sheets that are folded like accordions; the drug
should thus be a β-breaker,
a molecule that prevents proteins from folding into β-sheets.
In addition, the molecule must be small so that it can be absorbed by
the digestive tract after oral ingestion. It must also not be rapidly
degraded by the body and must be nontoxic.
small dipeptide—a molecule made of two amino acids—developed by Gazit’s
team meets all of these requirements: the nonphysiological amino acid α-aminoisobutyric
acid acts as a β-breaker,
and the second amino acid, D-tryptophan, contains an indole group, which is
an effective binder of aromatics. At the same time, D-tryptophan
stabilizes the dipeptide, because D-amino acids are broken down more
slowly in the body than are the physiological L-amino acids.
genetically altered mice with Alzheimer’s disease are treated with the
dipeptide, their disrupted cognitive functions normalize. A significant
decrease in the concentration of amyloid-forming β-peptides
and in the size of the plaques was found in the brains of these mice.