Researchers from Ecole Polytechnique Fédérale de Lausanne (EPFL) have found rendering mitochondria resistant to damage can stop Alzheimer’s disease and other diseases caused by amyloid toxicity. Alzheimer’s disease leads to dementia and is becoming more and more of a burden on healthcare systems. The disease is believed to be caused by an accumulation of toxic plaques in the brain and an abnormal aggregation of a beta-amyloid inside neurons. Previous research has looked into treatment for Alzheimer’s disease by reducing the formation of amyloid plaques. These results were not very promising and now researchers are looking for other treatment strategies such as considering Alzheimer’s disease as a metabolic disease.
The researchers looked at mitochondria, which are energy-producing powerhouses of cells, and important in metabolism. The researchers found that by boosting mitochondria defenses against a particular form of protein stress a reduction of the formation of amyloid plaques occurred in worms and mice. During normal aging and age-associated diseases including Alzheimer’s, cells face increasing damage and struggle to protect and replace dysfunctional mitochondria. By not having healthy mitochondria in Alzheimer’s disease brain damage can develop and lead to symptoms such as memory loss. The scientists identified two mechanisms that control the quality of mitochondria: 1) the “mitochondrial unfolded protein response” (UPRmt), which protects mitochondria from stress stimuli and 2) mitophagy, a process that recycles defective mitochondria. These mechanisms are very important to delaying or preventing mitochondrial damage during disease.
The team was interested in pharmacologically activating the mitochondria by testing established compounds, such as the antibiotic doxycycline and the vitamin nicotinamide riboside (NR). These compounds are known to turn on the two mechanisms that control the quality of mitochondria UPRmt and mitophagy in a worm model (C. elegans) of Alzheimer’s disease. After exposure to the drugs, the health, performance and lifespan of worms increased compared with untreated worms. Plaque formation was also found to be reduced in the worms who received the drugs. Further, the researchers used the same drugs to turn on mitochondrial defense pathways in cultured human neuronal cells and saw similar improvements. The results then led the researchers to test NR in a mouse model of Alzheimer’s disease. The mice saw improvement of mitochondrial function and a reduction in the number of amyloid plaques, which was the same result as found in the worms. The researchers also saw a normalization of the cognitive function in mice.
Alzheimer’s disease is thought by most to be the result of accumulation of amyloid plaques in the brain. The researchers in this study have shown that restoring mitochondrial health reduces plaque formation and improves brain function. The researchers feel that their result can help lead to a therapeutic approach to slow down the progression of neurodegeneration in Alzheimer’s disease, and possibly even in other disorders with mitochondrial and metabolic defects. By targeting mitochondria, NR, and other molecules that stimulate ‘defense and recycle’ systems perhaps Alzheimer’s disease can be stopped and prevented.
Source: Vincenzo Sorrentino and et al., Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity, Nature, 2017.