Inhibiting an interaction between two specific proteins may be a new way to target dementia. A recent study using a fruit fly model could help to design a way of slowing the progression of Alzheimer’s and other neurodegenerative diseases.
An estimated 1 in 3 seniors dies with one form of dementia. Affecting more than 5 million people in the United States, Alzheimer’s disease is the most common form of dementia; it accounts for well over half of all cases.
Alzheimer’s is characterized by an accumulation of amyloid plaques between nerve cells. Amyloid is a protein found in healthy brains. In Alzheimer’s, however, the protein is folded incorrectly, creating a form known as beta-amyloid, which is toxic to brain cells.
Despite decades of research, medical interventions that halt or slow this progressive, degenerative condition have not yet been found.
A recent study, conducted at University College London in the United Kingdom by Fiona Kerr and Linda Partridge, set out to look at potential drug targets using a fruit fly model.
“As our population ages, the incidence of dementia is increasing dramatically,” says Kerr, “and there is an urgent need to find new drugs to protect nerve cells and halt the progression of the disease.”
Specifically, the team investigated the interaction between two proteins known as Keap1 and Nrf2.
Nrf2 is a transcription factor that helps to mobilize genes important in cellular defense, such as antioxidant enzymes, drug metabolizing enzymes, and enzymes that repair or remove faulty DNA and proteins. In this way, the protein protects cells in stressful conditions, such as after injury or during inflammation.
The Nrf2 protein is found in much lower levels than normal in individuals with Alzheimer’s. This reduction in Nrf2 has made it a target for research into possible Alzheimer’s drugs. However, earlier attempts to activate Nrf2 have caused “off-target” toxic side effects by interacting with other proteins and enzymes.
To investigate this potential drug target from a slightly different angle, the current project used a fruit fly model to study another protein called Keap1, which naturally inhibits Nrf2.
They found that by blocking Keap1 from interacting with Nrf2, they could prevent the negative effects of the amyloid-beta protein.
The team also investigated the Keap1-Nrf2 disruptor in mouse neurons and found that it prevented amyloid toxicity in these cells, too. The authors conclude:
“Our findings provide compelling support for the use of direct Keap1-Nrf2 inhibitors for the treatment of neurodegenerative diseases, particularly AD [Alzheimer’s disease]. Future work is warranted to develop these compounds further for in vivo use, and to investigate their effects in combination with other established therapeutic targets for AD.”
The findings, published in PLOS Genetics, are the first to demonstrate that increasing levels of Nrf2 by impeding its inhibitor can protect mice from the detrimental effects of Alzheimer’s amyloid-beta plaques.
There is hope that by targeting this interaction between the two proteins, new drugs might be designed that slow or even halt the progression of Alzheimer’s. Because Nrf2 has a neuroprotective role, this pathway might also be useful in the treatment of other neurodegenerative conditions. In fact, levels of the protein are known to be reduced in amyotrophic lateral sclerosis, another neurodegenerative condition.
Fiona Kerr says: “Our work is the first step in identifying Keap1 as an effective target to prevent neuronal damage in Alzheimer’s. The humble fruit fly is a powerful tool to identify new genetic causes of human diseases, including neuronal degeneration, and our study demonstrates that these findings have the potential to lead to the development of new compounds that are effective in mammalian systems.”
The next step, of course, is to identify whether this approach will work in whole organisms and whether it might be effective at preventing the human nerve cell damage seen in Alzheimer’s. No doubt, experts will be watching the next phases of this line of investigation with interest.
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