Healthy mitochondria could stop Alzheimer's

December 6, 2017, Ecole Polytechnique Federale de Lausanne
Whole-brain hemisphere sections of Alzheimer's mice, the model APP/PSEN1, before and after treatment with the NAD+ booster Nicotinamide riboside (NR). The beta-amyloid plaque content in the brain of the APP/PSEN1 mice (left), clearly visible by Thioflavin S staining in green color and associated to brain damage during the disease, is reduced after 10 weeks treatment with NR (right). Credit: Vincenzo Sorrentino, Mario Romani, Francesca Potenza/EPFL.

Alzheimer's disease is the most common form of dementia and neurodegeneration worldwide. A major hallmark of the disease is the accumulation of toxic plaques in the brain, formed by the abnormal aggregation of a protein called beta-amyloid inside neurons.

Still without cure, Alzheimer's poses a significant burden on public health systems. Most treatments focus on reducing the formation of amyloid plaques, but these approaches have been inconclusive. As a result, scientists are now searching for alternative treatment strategies, one of which is to consider Alzheimer's as a metabolic disease.

Taking this line of thought, Johan Auwerx's lab at EPFL looked at , which are the energy-producing powerhouses of cells, and thus central in metabolism. Using worms and mice as models, they discovered that boosting mitochondria defenses against a particular form of protein stress, enables them to not only protect themselves, but to also reduce the formation of amyloid plaques.

During normal aging and age-associated diseases such as Alzheimer's, cells face increasing damage and struggle to protect and replace dysfunctional mitochondria. Since mitochondria provide energy to brain cells, leaving them unprotected in Alzheimer's disease favors brain damage, giving rise to symptoms like memory loss over the years.

The scientists identified two mechanisms that control the quality of mitochondria: First, the "mitochondrial unfolded protein response" (UPRmt), which protects mitochondria from stress stimuli. Second, mitophagy, a process that recycles . Both these mechanisms are the key to delaying or preventing excessive mitochondrial damage during disease.

While we have known for a while that mitochondria are dysfunctional in the brains of Alzheimer's patients, this is the first evidence that they actually try to fight the disease by boosting quality control pathways. "These defense and recycle pathways of the mitochondria are essential in organisms, from the worm C. elegans all the way to humans," says Vincenzo Sorrentino, first author of the paper. "So we decided to pharmacologically activate them."

The team started by testing well-established compounds, such as the antibiotic doxycycline and the vitamin nicotinamide riboside (NR), which can turn on the UPRmt and mitophagy defense systems in a worm model (C. elegans) of Alzheimer's disease. The health, performance and lifespan of worms exposed to the drugs increased remarkably compared with untreated worms. Plaque formation was also significantly reduced in the treated animals.

And most significantly, the scientists observed similar improvements when they turned on the same mitochondrial defense pathways in cultured human neuronal cells, using the same drugs.

The encouraging results led the researchers to test NR in a mouse model of Alzheimer's disease. Just like C. elegans, the mice saw a significant improvement of mitochondrial function and a reduction in the number of amyloid plaques. But most importantly, the scientists observed a striking normalization of the cognitive function in the mice. This has tremendous implications from a clinical perspective.

According to Johan Auwerx, tackling Alzheimer's through mitochondria could make all the difference. "So far, Alzheimer's disease has been considered to be mostly the consequence of the accumulation of in the brain," he says. "We have shown that restoring mitochondrial health reduces - but, above all, it also improves brain function, which is the ultimate objective of all Alzheimer's researchers and patients."

The strategy provides a novel therapeutic approach to slow down the progression of neurodegeneration in Alzheimer's disease, and possibly even in other disorders such as Parkinson's disease, which is also characterized by profound mitochondrial and metabolic defects.

The approach remains to be tested in human patients. "By targeting mitochondria, NR and other molecules that stimulate their 'defense and recycle' systems could perhaps succeed where so many drugs, most of which aim to decrease , have failed," says Vincenzo Sorrentino.

Explore further: Vitamin C deficiency and mitochondrial dysfunction in Alzheimer's disease

More information: Vincenzo Sorrentino et al, Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity, Nature (2017). DOI: 10.1038/nature25143

Related Stories

Vitamin C deficiency and mitochondrial dysfunction in Alzheimer's disease

December 4, 2017
Early clinical features of sporadic Alzheimer's disease include alterations in mitochondrial function that appear prior to classical features. Mitochondrial dysfunction increases the production of reactive oxygen species ...

Gene defect may point to solution for Alzheimer's

April 13, 2016
Alzheimer's disease is caused by protein (amyloid) deposition in the brain. New research at the University of Bergen (UiB) and Haukeland University Hospital shows that the protein PITRM1, which is found in mitochondria, otherwise ...

Overactive scavenger cells may cause neurodegeneration in Alzheimer's

June 30, 2017
For the first time, researchers from the University of Zurich demonstrate a surprising effect of microglia, the scavenger cells of the brain: If these cells lack the TDP-43 protein, they not only remove Alzheimer's plaques, ...

Key cellular auto-cleaning mechanism mediates the formation of plaques in Alzheimer's brain

October 3, 2013
Autophagy, a key cellular auto-cleaning mechanism, mediates the formation of amyloid beta plaques, one of the hallmarks of Alzheimer's disease. It might be a potential drug target for the treatment of the disease, concludes ...

Recommended for you

Rocky start for Alzheimer's drug research in 2018

January 19, 2018
The year 2018, barely underway, has already dealt a series of disheartening blows to the quest for an Alzheimer's cure.

Alzheimer's disease: Neuronal loss very limited

January 17, 2018
Frequently encountered in the elderly, Alzheimer's is considered a neurodegenerative disease, which means that it is accompanied by a significant, progressive loss of neurons and their nerve endings, or synapses. A joint ...

Anxiety: An early indicator of Alzheimer's disease?

January 12, 2018
A new study suggests an association between elevated amyloid beta levels and the worsening of anxiety symptoms. The findings support the hypothesis that neuropsychiatric symptoms could represent the early manifestation of ...

One of the most promising drugs for Alzheimer's disease fails in clinical trials

January 11, 2018
To the roughly 400 clinical trials that have tested some experimental treatment for Alzheimer's disease and come up short, we can now add three more.

Different disease types associated with distinct amyloid-beta prion strains found in Alzheimer's patients

January 9, 2018
An international team of researchers has found different disease type associations with distinct amyloid-beta prion strains in the brains of dead Alzheimer's patients. In their paper published in Proceedings of the National ...

Advances in brain imaging settle debate over spread of key protein in Alzheimer's

January 5, 2018
Recent advances in brain imaging have enabled scientists to show for the first time that a key protein which causes nerve cell death spreads throughout the brain in Alzheimer's disease - and hence that blocking its spread ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

betterexists
1 / 5 (1) Dec 06, 2017
Better News Today: (For 1st time, 1 DNA Sequenced) Lakhs of Mitochondria WITHIN ANY CELL contain DIFFERENT DNA (Actually More than 10 DNA types in Each Mitochondrion of a cell itself) ! Knowing How & Why will help HUMANITY in future. So, WHY NOT Transfer Mitochondrial Contents of 1 Body Cell Type into Another; From 1 Mouse into a Rat AND See The Effects. https://www.eurek...0517.php

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.