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Can lichen compound forestall Alzheimer’s neuron-destruction? Chemical cousin in human trials now

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Research is beginning to indicate that the culprit in Alzheimer’s, Parkinson’s, and other diseases is the activity of tiny bits of misfolded amyloid-beta protein (small protein aggregates), which have a toxic, destructive effect on neurons.

Now a team of researchers in Berlin have found that orcein, historically a red lichen-derived food and fabric color, appears to reduce the abundance of these toxic bits (called precursors because they eventually lead to large plaques). Both orcein and O4, a small blue pigment molecule similar to one in the complex 14-molecule orcein compound, bind to the pre-fibrous amyloid-beta aggregates, transforming them to large plaques which are not thought to be neurotoxic.

Protein Misfolding is a Multistep Process

As lead authors Dr. Jan Bieschke and Prof Erich E Wanker explain in a report published Dec 2 by Nature Chemical Biology, protein misfolding is considered to be the cause of Alzheimer’s, Parkinson’s and also Huntington’s disease.

In a multistep process, proteins misfold and accumulate into large extra- or intracellular plaques. Researchers assume that small misfolded protein aggregates that are precursors of mature plaques are toxic for nerve cells and are the reason why they are eventually destroyed.

Dye from the Canary Islands

Eight years ago Prof Wanker screened hundreds of natural compounds to find potential candidate drug molecules for the treatment of neurodegenerative diseases. Among those substances he found orcein, a compound and isolated from lichens that grow in the Canary Islands & elsewhere that is made up of about 14 small molecules.

As these molecules might have different biological effects, the researchers began to search for pure chemicals with similar properties. They identified the substance O4, a blue dye, which is structurally very similar to one of the 14 orcein molecules.

Moreover, they showed that O4 stimulates the formation of large, non-toxic protein plaques from small toxic protein assemblies.

A New Mechanism for Eliminating Toxic Aggregates

A few years ago Prof Wanker and his colleagues had discovered that EGCG (Epigallocatechin-3-gallate), a natural chemical compound found in green tea, renders toxic protein assemblies non-toxic.

With orcein and O4, the researchers have now found another mechanism to eliminate small toxic protein aggregates. However, instead of remodeling protein plaques, the dyes reduce the abundance of small, toxic precursor protein assemblies by accelerating the formation of large plaques, as the researchers could now show in their laboratory.

“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.”

The synthetic dye methylene blue is already being tested in clinical trials. This dye also seems to stimulate the formation of large plaques in a way similar to O4.

Other therapeutic approaches tested in clinical trials which aim at eliminating small precursor aggregates have so far not led to a significant improvement of disease symptoms.

Therapeutic Benefit Remains to Be Seen

However, it still remains to be seen whether the blue dye O4 can also be effective against small amounts of misfolded proteins in the brains of Alzheimer’s patients – and whether the accelerated formation of larger plaques can indeed reduce the signs and symptoms of Alzheimer’s disease in humans.

Further studies will be necessary to address the question of whether the accelerated formation of large plaques can be a therapeutic approach. “We hope that our findings will stimulate research activities in this direction, especially in drug discovery,” Prof Wanker said.

Source: Nature Chemical Biology article, press release, Dec 2, 2011

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