LONDON – Any signs of neurodegeneration in a mouse model of Alzheimer’s disease can be halted with a compound that can be taken by mouth, a new study has shown.

The drug, which was originally developed for another purpose, inhibits a metabolic pathway in the brain called the unfolded protein response (UPR). Normally, the UPR transiently shuts down protein production when abnormal proteins are produced.

Because the UPR is thought to be overactive in a range of neurodegenerative diseases, including Parkinson’s disease, amyotrophic lateral sclerosis and prion diseases, as well as Alzheimer’s disease, drugs that inhibit it may have the potential to treat all those conditions.

Giovanna Mallucci, program leader at the Medical Research Council (MRC) Toxicology Unit in Leicester, UK, told BioWorld Today: “One reason why this research is so important is that it represents a completely original approach to how neurodegenerative diseases are studied, looking at what actually goes wrong in the brain cells. We were extremely excited when we saw the treatment stop the disease in its tracks and protect brain cells, restoring some normal behaviors and preventing memory loss in the mice.”

Although a drug for use in humans affected by neurodegenerative disease is still a long way off, she said, the study provides proof of principle that inhibiting the UPR is a useful drug target. “This compound had serious side effects. But the fact that we have established that this pathway can be manipulated to protect against brain cell loss means that developing drug treatments targeting this pathway for prion and other neurodegenerative diseases is now a real possibility,” Mallucci said.

The team now wants to try to develop compounds that will target the UPR pathway. “We hope to find candidate drugs that are less toxic than the substance we used in our study, and therefore could potentially be used in humans,” Mallucci said. “In addition, we would like to develop ways of detecting neurodegenerative diseases early on, so that it is possible to prevent their development.”

An account of the study appears in the Oct. 9, 2013, issue of Science Translational Medicine in a paper, titled “Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice.”

A buildup of misfolded proteins in the brain is typical of several neurodegenerative diseases, including Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and prion diseases. Yet the search for the exact cause of the death of neurons that also occurs in those illnesses had drawn a blank – until Mallucci and her colleagues showed last year that the accumulation of misfolded prion protein in the brains of mice leads to neurodegeneration by disturbing the normal regulation of protein production in brain cells.

In order to function, proteins need to be folded correctly. If the endoplasmic reticulum of the cell detects proteins that are wrongly folded or not folded at all, the cell triggers the UPR pathway. One outcome can be that the cell shuts down all protein synthesis. It does that by phosphorylating, and therefore activating a molecule called PERK. Activated PERK, in turn, phosphorylates and activates a subunit of another molecule, called eIF2a-P. Activation of eIF2a-P has the effect of inhibiting the initiation of translation, thus stopping protein production.

Under normal circumstances, that shutdown would not last very long and protein production would begin again – but in the continued presence of misfolded proteins, protein production stays firmly switched off. As a result, key proteins crucial for the survival of nerve cells stop being made.

In an earlier study, Mallucci and her team injected a protein into the brains of mice, which prevented activation of eIF2a-P and therefore kept protein production switched on. They found that the neurodegeneration that they would normally expect in those mice was prevented.

In the study reported in Science Translational Medicine, the researchers take their work one step further, by using an oral compound, originally developed by GlaxoSmithKlin plc for another purpose. That compound, called GSK2606414, was given to the mice orally, and tests showed that it passed through the blood-brain barrier.

Using mice that were inoculated with prion protein, which are acknowledged to be a good model for human neurodegenerative disorders, including Parkinson’s and Alzheimer’s, the scientists observed what happened when they gave the animals the drug either soon after the onset of disease or later, when neurodegenerative symptoms had developed fully. In both cases, they found that the animals recovered from behavioral abnormalities, that there was no progression in physical brain abnormalities and that loss of neurons was halted.

Controls included mice that were given an inert compound (vehicle) but no drug.

Writing in Science Translational Medicine, Mallucci and her co-authors reported that there was an “absence of clinical prion disease in all treated mice at a time when vehicle-treated controls were all terminally ill with the disease.”

Mallucci said: “Unfortunately, we were not able to study the treated mice for longer, as they lost more than 20 percent of their body mass by 12 weeks after inoculation, and in order to comply with UK Home Office regulations, they therefore had to be culled.” The animals also had raised blood sugar levels.

Commenting on the study, Hugh Perry, chair of the MRC’s Neuroscience and Mental Health Board, said: “Despite the toxicity of the compound used, this study indicates that, in mice at least, we now have proof of principle of a therapeutic pathway that can be targeted. This might eventually aid the development of drugs to treat people suffering from dementias and other devastating neurodegenerative diseases.”