Schematic illustration of the drug discovery strategy described in this work. The strategy consists of four steps: (1) A fragment-based approach that allows the identification of small molecules that interact with the aggregation-prone system, here Aβ42, including FDA-approved molecules for drug repurposing. (2) An in vitro kinetic analysis that identifies the specific molecular steps in the Aβ42 aggregation mechanism responsible for the generation of toxic species. (3) A further kinetic analysis to determine the mechanism of inhibition associated with the molecules identified in step 1. (4) An evaluation of the effects of these molecules on the formation of toxic species in vivo. In particular, the inhibition of primary nucleation is predicted to delay the aggregation without affecting the total number of oligomers generated by the aggregation process, whereas inhibiting elongation or secondary nucleation is predicted either to increase or to decrease the number of toxic oligomers, respectively.
Researchers have identified a drug that targets the first step in the toxic chain reaction leading to the death of brain cells, suggesting that treatments could be developed to protect against Alzheimer’s disease, in a similar way to how statins are able to reduce the risk of developing heart disease. The drug, which is an approved anti-cancer treatment, has been shown to delay the onset of Alzheimer’s disease, both in a test tube and in nematode worms. This is the first time that a potential ‘neurostatin’ has been reported.
When the drug was given to nematode worms genetically programmed to develop Alzheimer’s disease, it had no effect once symptoms had already appeared. But when given to worms before any symptoms became apparent, no evidence of the condition appeared. By analysing the way the drug bexarotene, works at the molecular level, the international team found it stops the first step in the molecular cascade that leads to the death of brain cells. This step, called primary nucleation, occurs when naturally occurring proteins in the body fold into the wrong shape and stick together with other proteins, eventually forming amyloid fibrils. This process also creates smaller clusters called oligomers, which are highly toxic to nerve cells and are thought to be responsible for brain damage in Alzheimer’s disease.
Bexarotene delays Aβ42 fibril formation in a label-free environment.
They determined what happens during each stage of the disease’s development, and also what might happen if one of those stages was somehow switched off. “In order to block protein aggregation, we need accurate understanding of exactly what is happening and when,” said Vendruscolo. “The test that we have developed not only measures the rates of the process as a whole, but also the rates of its specific component sub-processes, so that we can reduce the toxicity of the aggregates rather than simply stopping them forming.”
Johnny Habchi et al assembled a library of more than 10,000 small molecules which interact in some way with amyloid-beta. Using the test developed by Knowles and Linse, they analysed molecules that were either drugs already approved for some other purpose, or drugs developed for Alzheimer’s disease or similar conditions that failed clinical trials. The first successful molecule they identified was bexarotene, which is approved for lymphoma treatment. “…what it does is suppress primary nucleation, which is the aim for any neurostatin-type molecule,” said Vendruscolo. “If you stop the process before aggregation has started, you can’t get proliferation.”
By exploiting their novel approach, which enables them to carry out highly quantitative analysis of the aggregation process, the researchers have now shown that compounds such as bexarotene could instead be developed as preventive drugs, because its primary action is to inhibit the crucial first step in the aggregation of amyloid-beta. “A recent clinical trial of bexarotene in people with Alzheimer’s was not successful, but this new work in worms suggests the drug may need to be given very early in the disease. We will now need to see whether this new preventative approach could halt the earliest biological events in Alzheimer’s and keep damage at bay in in further animal and human studies.”
Over the next 35 years, the number of people with Alzheimer’s disease is predicted to go from 40 million to 130 million, with 70% of those in middle or low-income countries. “The only way of realistically stopping this dramatic rise is through preventive measures: treating Alzheimer’s disease only after symptoms have already developed could overwhelm healthcare systems around the world.”…”The next target of our research is also to be able to treat victims of this dreadful disease,” said Vendruscolo. http://www.cam.ac.uk/research/news/researchers-identify-neurostatin-that-may-reduce-the-risk-of-alzheimers-disease
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