Scientists at the École polytechnique fédérale de Lausanne (EPFL) have found a way to make mitochondria more resistant to damage, which could potentially be used to halt Alzheimer’s and other, similar, diseases.
Globally, Alzheimer’s disease is the most common form of dementia and cause of neurodegeneration. It causes brain damage and symptoms such as long-term memory loss. It is an amyloid-based disease, with the characteristic hallmark being the formation of toxic plaques in the brain made from the aggregated beta-amyloid inside the neurons.
Improving mitochondrial quality control
Diseases like Alzheimer’s are the result of the loss of proteostasis, which leads to the creation of sticky misfolded proteins, which form plaques by bonding together. There is still no cure for the disease, and it causes tremendous suffering while posing a considerable burden on the public health system. Many treatments have focused on trying to reduce the formation of the plaques, but, as of yet, the results are inconclusive. One group of researchers has tried a different approach and is looking at Alzheimer’s as a metabolic disease.
The new study focused on the mitochondria, the powerhouses of the cell that produce the energy needed for cellular functions central to metabolism[1]. The research team showed that in worms and mice, they could make the mitochondria more robust and resistant to a particular form of protein stress, allowing them to better protect themselves and, more importantly, reduce the accumulation of amyloid plaques.
During the aging process, cells are exposed to increased levels of damage, and that includes damage to their mitochondria. Damaged mitochondria become dysfunctional, and cells normally replace them via a process known as mitophagy, a selective degradation of the mitochondria by autophagy.
Unfortunately, over time, our cells become increasingly poor at removing these problem mitochondria, thus leaving them vulnerable to Alzheimer’s disease.
The researchers identified two key processes that act as a quality control system for the mitochondria. First, there is the process of mitophagy, which recycles damaged mitochondria, and second, there is the mitochondrial unfolded protein response (UPRmt), which shields mitochondria from stress. Taken together, these processes are one possible solution to reducing mitochondrial damage and could help combat diseases like Alzheimer’s.
Better recycling improves cognition
It has been known for some time that the mitochondria are dysfunctional in the brains of Alzheimer’s patients, but this is the first evidence suggesting that the disease might be combated by boosting these quality control systems. These two processes are present in C.elegans flatworms, mice, and humans, so worm and mouse research could translate well into human beings. The researchers decided to try activating these systems using a drug to see if they could boost protection and quality control in the mitochondria.
They used the antibiotic doxycycline and the vitamin nicotinamide riboside (NR), both known to activate the UPRmt and mitophagy systems in worm models of Alzheimer’s. They noticed that the health and lifespan of treated worms increased dramatically compared with untreated controls, and the formation of plaques was also significantly reduced. Intriguingly, they also observed similar improvements when they activated the same two systems in human neuronal cells in culture using the same two drugs.
Finally, the researchers tested NR in a mouse model of Alzheimer’s disease. They observed the same improvement to mitochondrial function and reduction of plaques as seen in the flatworms. Perhaps most importantly, the researchers noted a dramatic improvement in the cognitive function of the mice.
Conclusion
The usual caveats apply; the results are only so far confirmed in flatworms, Alzheimer’s model mice and human cells in culture. However, the two target quality control systems are present in all three species and can be activated in the same way, which leaves some room for optimism. Will it prove to be more effective than the direct removal of amyloids? Or could it even be a co-therapy for those other approaches? Only time and a clinical trial will tell.
Literature
[1] Vincenzo Sorrentino, Mario Romani, Laurent Mouchiroud, John S. Beck, Hongbo Zhang, Davide D’ Amico, Norman Moullan, Francesca Potenza, Adrien W. Schmid, Solène Rietsch, Scott E. Counts, Johan Auwerx.Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature 06 December 2017. DOI: 10.1038/nature25143.
