Study Identifies a Promising Therapeutic Target for Alzheimer’s Disease

As our regular readers know by now, Alzheimer’s disease is characterized by the buildup of a toxic protein called amyloid-beta in the brain. While amyloid-beta was considered for many years to be the primary driver of the disease, we now know that the full picture is much more nuanced, with many different genes likely involved (see The Genetics of Alzheimer’s Disease). One of the genes that is often inhibited in people with Alzheimer’s disease is Nrf2. Nrf2 is a transcription factor, meaning it can control which other genes are turned on or off in a cell. In particular, Nrf2 is important for controlling cellular defense genes, including genes responsible for antioxidant activity and DNA repair. It’s been shown in mice that increasing the levels of Nrf2 in the brain can improve the symptoms and pathology of Alzheimer’s disease.

Several drugs have been designed to activate Nrf2 in the hopes that this could help treat Alzheimer’s and other neurodegenerative conditions. While these drugs were effective in mouse models of the disease, they were often toxic in humans. To address this problem, a group of researchers in England decided to try a different approach by targeting two proteins called GSK-3 and Keap1. These proteins are produced in normal human cells and act as inhibitors of Nrf2. Thus, the researchers hoped that by blocking GSK-3 or Keap1, they might be able to indirectly activate Nrf2.

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Nrf2 is a type of enzyme called a transcription factor. Inhibitor molecules, such as GSK-3 and Keap1, can bind to Nrf2 and prevent it from functioning. Thus, blocking these inhibitors could increase the activity of Nrf2. Image Source

Their results were published last week in PLoS Genetics. The study utilized fruit flies as a model of Alzheimer’s disease. When the flies were treated with lithium, which can act as a GSK-3 inhibitor, the defects in Nrf2 activity were not resolved. However, the results for the Keap1 inhibitor were much more promising. Not only was Nrf2 activity returned to normal levels, but the flies also experienced reduced toxicity of the amyloid-beta protein. The researchers even observed increased degradation of amyloid-beta, helping to reduce the levels of this protein in the brain. Similar protective effects were observed when neurons cultured from mouse brains were treated with a drug to block the interaction between Keap1 and Nrf2.

This study provides strong evidence for Keap1 as a possible therapeutic target in Alzheimer’s disease. By blocking Keap1, it may be possible to increase the activity of Nrf2 and in turn the activation of cellular defense genes, protecting our brains from neurodegenerative diseases like Alzheimer’s. The authors also suggested that a combined treatment for both Keap1 and GSK-3 may have added benefits. While the neuroprotective effects GSK-3 inhibition seem to involve a mechanism independent of Nrf2, the mice treated with both Keap1 and GSK-3 inhibitors fared better than those treated with either drug alone.

Targeting cell defense pathways like Nrf2 may provide a more effective treatment method than those previously attempted. The majority of past studies have tried to directly remove amyloid-beta from the brain, yet these drugs have been a resounding failure in humans (see Where’s our cure to Alzheimer’s disease?) The Keap1 and GFK-3 inhibitors are different, in that their main action is not to remove amyloid-beta but simply to reduce its toxicity. Future research will investigate the safety and efficacy of these drugs in humans.

 

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One thought on “Study Identifies a Promising Therapeutic Target for Alzheimer’s Disease

  1. Pingback: Study Identifies a Promising Therapeutic Target for Alzheimer’s Disease | AlzScience | Fighting alzheimer's disease

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