A German research team has recently uncovered evidence that orcein, a compound used for hundreds of years as a food dye, and the related compound O4 both act to accelerate the aggregation of β-amyloid monomers into mature amyloid plaques.

While the exact physiological mechanisms through which the symptoms of Alzheimer’s Disease arise are largely unknown, it is commonly accepted that the development of several features in neuronal tissue, most notably neurofibrillary tangles and amyloid plaques, are commonly associated and directly correlated with progression of the disease. Though different types of amyloid plaques have been observed in a variety of neurodegenerative conditions, the type which are typically related to Alzheimer’s Disease consist of spherical accumulations of the protein β-amyloid. β-amyloid is a 39-43 amino acid peptide which is cleaved from the larger “amyloid precursor protein,” a membrane protein with little-understood function.

Though it was originally assumed that these protein monomers aggregate to form mature amyloid fibrils which are cytotoxic to nearby cells, a growing body of evidence seems to suggest that a variety of precursor molecules may instead be responsible for this toxicity. These precursors take many forms, but typically consist of a variety of β-amyloid oligomers or “proto-fibrils,” and can be thought of as intermediate structures which are formed as β-amyloid protein monomers are progressively aggregated into mature amyloid fibrils.

By using either orcein (a dye extracted from lichens) or O4*, a molecule with similar structure, the research team has shown that the efficiency of the biochemical pathways leading from single β-amyloid proteins to mature, ordered β-amyloid fibrils can be increased, resulting in lower concentrations of these potentially toxic side products.

The researchers were able to demonstrate that O4 affects this efficiency by binding directly to the hydrophobic segments of individual β-amyloid proteins which seem to be responsible for aggregation and mature plaque formation. They suggest that this association accelerates the conversion of monomers and oligomers into amyloid fibrils by increasing their hydrophobicity, which should promote intermolecular association and aggregation.

Additionally, it was demonstrated that O4 appears to interact with mature amyloid fibrils as well, and that this interaction requires association with four or five different amyloid monomers at the same time. Again, this finding supports the idea that O4 could play an important therapeutic role in the stabilization of mature amyloid fibrils, and the acceleration of their formation. Ultimately, this acceleration could reduce the concentration of transient, soluble intermediate products which are available to pose a toxic effect to cells.

These new findings provide important insight into a potentially novel strategy for therapeutic intervention in Alzheimer’s disease. From the original press release (Dec 2nd, 2011):

“This is a new mechanism,” Professor Wanker explained. “Up to now it has been considered to be very difficult to stop the formation of small toxic protein assemblies. If our hypothesis is correct that the small aggregates, which are precursors of plaques, indeed cause neuronal death, with O4 we would have a new mechanism to attack the disease.” -Professor Erich Wanker, Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch

At this point, much is still unclear with regard to how much potential there is in targeting this amyloid fibrillogenesis process therapeutically, but several questions will certainly need to be addressed. Aside from assessing whether these chemical compounds can influence the aggregation of β-amyloid at low nanomolar concentrations in vivo, the question of whether such strategies would ultimately affect the progression of certain neurodegenerative disorders, including Alzheimer’s Disease, is still a matter of debate.

*O4 = 2,8-bis-(2,4-dihydroxy-phenyl)-7-hydroxy-phenoxazin-3-one.

Original Article: http://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.719.html

Original Press Release: http://www.mdc-berlin.de/en/news/2011/20111201-a_natural_dye_obtained_fr...