Healthy mitochondria could stop Alzheimer’s
December 6, 2017
Ecole Polytechnique Fédérale de Lausanne
Using a bioinformatics and experimental approach,
scientists have found that rendering mitochondria resistant to damage can halt
diseases caused by amyloid toxicity, such as Alzheimer’s disease.
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 mitochondria, 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 defective mitochondria. Both these
mechanisms are the key to delaying or preventing excessive mitochondrial damage
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 amyloid
plaques in the brain,” he says. “We have shown that restoring
mitochondrial health reduces plaque formation — 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 amyloid plaque formation, have failed,” says
Materials provided by Ecole Polytechnique
Fédérale de Lausanne. Note: Content may be edited for style and length.
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, 2017;