By boosting the activity of cellular ‘power stations’ in the brains of mice with a dementia-like condition, an international team of researchers has reversed pathological memory loss.
Problems with energy-producing cellular structures called mitochondria have previously been linked to neurodegenerative diseases such as Alzheimer’s. Before now, it wasn’t clear if this was a cause or a consequence of these conditions.
“This work is the first to establish a cause-and-effect link between mitochondrial dysfunction and symptoms related to neurodegenerative diseases, suggesting that impaired mitochondrial activity could be at the origin of the onset of neuronal degeneration,” says Giovanni Marsicano, a neuroscientist from the French National Institute of Health and Medical Research (INSERM).
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In order to establish that cause-and-effect link, the team developed a tool called mitoDREADD-Gs, which uses a drug called clozapine-N-oxide (CNO) to serve as an ignition switch for mitochondria.
The mitoDREADD-Gs mechanism was tested both in mice genetically modeled to have dementia-like symptoms and in human cells grown in the lab, showing that memory and motor problems caused by mitochondrial malfunction could be reversed.
What’s more, the researchers were able to administer drugs to the mice to limit mitochondrial activity and then remove those restrictions using mitoDREADD-Gs – further confirming the role of mitochondria in their symptoms of dementia.
While mitoDREADD-Gs itself isn’t a treatment, its role in experiments investigating mitochondrial activation provides useful lessons that future treatments could be based upon.
“Ultimately, the tool we developed could help us identify the molecular and cellular mechanisms responsible for dementia and facilitate the development of effective therapeutic targets,” says biologist Étienne Hébert Chatelain from the Université de Moncton in Canada.
Future steps suggested by the researchers include testing this approach with different types of neurodegenerative diseases and related issues like psychiatric disorders. After that, work can begin on developing safe drugs to take on the role of mitoDREADD-Gs in humans.
We know that the different types of dementia are incredibly complex in the way they get started and develop, and a whole host of risk factors are involved – so there’s value in tackling the problem from a range of different angles, including mitochondria.
The researchers also want to take a closer look at exactly how supercharging mitochondria might work over longer periods of time, which will be crucial in figuring out whether or not this is a genuine option for treating diseases such as Alzheimer’s.
“Our work now consists of trying to measure the effects of continuous stimulation of mitochondrial activity to see whether it impacts the symptoms of neurodegenerative diseases and, ultimately, delays neuronal loss or even prevents it if mitochondrial activity is restored,” says neuroscientist Luigi Bellocchio, from INSERM.
The research has been published in Nature Neuroscience.