Monthly Archives: March 2017

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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Autoimmune Diseases May Be Linked to Dementia

Our immune system is pretty great. It helps us recover from injury and fight off deadly pathogens. However, sometimes the immune system does its job a little too well. In certain autoimmune diseases, immune cells can mistakenly recognize a part of our own body as a foreign invader and start attacking it. Depending on what type of tissue is being targeted, autoimmunity can lead to a variety of conditions including rheumatoid arthritis, celiac disease, and multiple sclerosis. Approximately 50 million Americans (20% of the population) have an autoimmune disease.

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Some of the most common autoimmune diseases. Image Source

A study published this week in the Journal of Epidemiology and and Community Health looked at the relationship between autoimmune diseases and dementia. The researchers used health records of more than 1.8 million people in England who were hospitalized for an autoimmune condition between 1998 and 2012. They found that these patients were 20% more likely to be later hospitalized for dementia compared to controls. They identified 18 autoimmune diseases that were significantly associated with dementia. When they examined the type of dementia, the autoimmune patients were at the greatest risk for vascular dementia, with a 28% higher risk than normal. The increased risk for Alzheimer’s disease was relatively small at 6%.

This study is in line with several previous papers that hinted at a possible link between autoimmunity and dementia. It’s been shown that people with two common autoimmune diseases, type 1 diabetes and thyroid autoimmune disease, are at an increased risk of dementia. The mechanism for this connection remains unknown, but it raises the interesting question of whether dementia may be related to the immune system.

Additionally, the study supports the possible use of NSAIDs as a way to reduce the risk of dementia. NSAIDs (which include aspirin, ibuprofen, and naproxen) are some of the most commonly-used painkillers and can also be used to combat inflammation in autoimmune conditions. People who take NSAIDs tend to have a reduced risk of Alzheimer’s disease, suggesting that using these drugs to treat an overactive immune system could have cognitive benefits as well.

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Advil, Aleve, and Motrin are some of the most common NSAIDs available over-the-counter. Image Source

Many doctors have begun prescribing baby aspirins to their patients in the hopes of decreasing their risk of dementia as well as cardiovascular disease. However, caution is necessary when considering an NSAID regimen. It’s possible that for some people, NSAIDs could be doing more harm than good, as one study suggested that these drugs may reduce the risk of Alzheimer’s but increase the risk of vascular dementia. More research is needed before we can say conclusively whether NSAIDs may be beneficial for cognitive health.

 

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