Activating a cell-protecting protein could ward off Alzheimer's symptoms

Amyloid plaques in Alzheimer's disease
Blocking Keap1, an inhibitor of the protein Nrf2, shielded mouse neurons from the toxic effects of amyloid plaques in Alzheimer's disease (pictured).

University College London scientists have identified the inhibitor of a cell-protecting protein as a promising new target in treating Alzheimer’s disease. They tested the approach in fruit fly and mouse models and hope to translate their work to human nerve cells.

The protein, Nrf2, usually protects brain cells, but people with Alzheimer’s have less of it in their neurons than healthy people do. The team found that blocking the interaction between Nrf2 and its inhibitor, Keap1, staved off the damaging effects of amyloid-beta in the brains of fruit flies and mouse nerve cells, according to the statement. Amyloid-beta peptides accumulate into the toxic plaques that characterize Alzheimer’s disease.

The study, published in PLOS Genetics, is the first to show that blocking Keap1 to boost Nrf2 could shield mouse neurons from the negative effects of amyloid-beta plaques. The research suggested the Keap1/Nrf2 interaction as a target for new Alzheimer's drugs that could potentially have fewer side effects, according to the statement.


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"Our findings are important because chemicals that block Keap1 increase activity of a cell protective protein called Nrf2, and so they have potential to prevent this nerve cell loss in Alzheimer's disease and other forms of dementia,” said Fiona Kerr, who led the team alongside Linda Partridge, in the statement.

Developing a drug that prevents neuron loss would be a game changer for Alzheimer’s, where treatments focus on controlling symptoms, but do not delay or halt progression of the disease. A number of biotech and pharma companies are working on Alzheimer’s treatments, but several have suffered late-stage failures.

Eli Lilly abandoned its amyloid-binding solanezumab in November, after Phase 3 data showed patients treated with the drug had no significant slowing in cognitive decline compared to placebo. In January, Merck shut down a 2,000-patient phase 2/3 trial of its BACE inhibitor, verubecestat, after external reviewers found it had “virtually no chance of finding a positive clinical effect.” And just this week, Accera’s candidate missed its primary endpoint in a phase 3 trial.

Focusing on Nrf2 could prove to be a more effective way of controlling amyloid-beta.

“More work is now required to develop these Keap1-Nrf2 disrupting chemicals as drugs for use in whole organisms and to test whether this approach can protect human nerve cells from the damage associated with Alzheimer's,” Kerr said.

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