Alzheimer’s disease is a chronic condition in which a person’s cognitive functions, such as memory, language, and mood, decline with increasing age. A hallmark feature of Alzheimer’s is the presence of plaques in the brain, which are made of a toxic protein called Aβ. Right now, there are no treatments that prevent the build up of this damaging protein or reduce its effects on people with Alzheimer’s disease.
To find treatments, researchers often compare protein and gene levels in people with disease to those who don’t have it (the control population). This type of experiment can provide clues to the processes that happen in the disease state, which can then be targeted by therapeutics to return them to “normal” or the way that they function in people without the disease. Using these approaches, a team of researchers led by Johan Auwerx, Professor at the École Polytechnique Fédérale and Nestle Chair in Energy Metabolism in Lausanne, Switzerland, uncovered new processes that underlie Alzheimer’s disease, which may be targeted by therapeutics to reduce or prevent the accumulation of damaged or toxic protein.1 The results of this research published recently in Nature.
The researchers analyzed genetic markers of mitochondrial function in brain samples from Alzheimer’s patients and found that several different brain regions showed reduced activity of the energy generating reactions that occur in the mitochondria. In addition to lower energy production, gene functions that help the mitochondria manage stress were increased in Alzheimer’s patients compared to healthy controls. These changes suggested that cells in Alzheimer’s patients were making less energy and that they “felt stressed,” particularly by imbalanced or abnormal protein levels. Similar genetic changes were detected in mouse and worm models of Alzheimer’s disease, allowing the researchers to define a mitochondrial stress response “MSR” signature of genes that are altered in Alzheimer’s disease in humans and animals.
To learn more about the role of MSR in Alzheimer’s disease, the researchers used techniques to either increase or decrease function of the MSR pathways in worm and mouse models. Through these experiments they were able to demonstrate that increasing activity of the MSR led to a state in which cells maintain a healthy balance of protein. This cellular function is especially important, as cells are constantly generating, degrading, and recycling proteins, so the controls over these processes have be constantly tuned to meet the cellular needs. Through their experiments altering function of the MSR, the researchers found that, in addition to providing protection against Alzheimer’s disease, the MSR also regulated health and lifespan in model organisms.
In prior work, the researchers showed that nicotinamide riboside (NR), a B3 vitamin known to raise cellular nicotinamide adenine dinucleotide (NAD) levels in mice and humans,2, controlled many of the same functions as the MSR, namely mitochondrial function and health and lifespan in mice.3 To extend that work and determine if there were connection between NR and the MSR, they treated Alzheimer’s models with NR and looked for beneficial effects. These experiments showed that NR was able to restore health and lifespan in a population of worms that normally exhibited reduced health and longevity due to genetic changes. When the researchers treated mice that model Alzheimer’s disease, they showed NR reduced deposits of the toxic Aβ protein in the brain. Mice treated with NR also displayed signs of increased MSR function. Together, these changes resulted in improved memory in treated mice.
Through this study, Auwerx and colleagues demonstrated that alteration of the MSR pathway can help prevent accumulation of toxic protein in the brain and that NR may provide protection against Alzheimer’s disease because it can “turn on” the MSR. Much more research is needed to fully understand the mechanisms by which NR alters the MSR and what the benefits NR may hold for people with Alzheimer’s, but these data are the essential first steps toward investigating NR as a potential treatment for Alzheimer’s and other age-associated diseases caused by accumulation of toxic protein.
- Sorrentino, V., et al., Enhancing mitochondrial proteostasis reduces amyloid-beta proteotoxicity. Nature, 2017.
- Trammell, S.A., et al., Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun, 2016. 7: p. 12948.
- Zhang, H., et al., NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science, 2016. 352(6292): p. 1436-43.