Boosting mitophagy — a natural process that clears neurons from damaged mitochondria (cells’ energy powerhouses) — decreased amyloid plaque formation and reversed cognitive deficits, namely memory impairments, across different animal models of Alzheimer’s disease (AD).
“When the cleaning system does not work properly, there will be an accumulation of defective mitochondria in the brain cells. And this may be really dangerous. At any rate, the poor cleaning system is markedly present in cells from both humans and animals with Alzheimer’s. And when we improve the cleaning in live animals, their Alzheimer’s symptoms almost disappear,” Vilhelm Bohr, study co-lead author, said in a press release. Bohr is affiliate professor at the Center for Healthy Aging and National Institutes of Health.
The study “Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease” was published in the journal Nature Neuroscience.
Mitochondria provide the energy necessary for neurons’ survival and optimal function. Not surprisingly, accumulation of damaged mitochondria is seen in sporadic and familial forms of Alzheimer’s disease, and in mouse models of the disease.
To prevent the accumulation of damaged mitochondria, cells have a cleaning processes called mitophagy that, once activated, targets damaged mitochondria to degradation and recycling.
However, the role of mitophagy in AD progression is unclear.
An international team of researchers looked closely at post-mortem brain tissue samples from the hippocampus — a region in the brain linked to memory and spatial navigation — of AD patients and from AD iPSC-derived neurons and saw accumulation of damaged mitochondria due to defective mitophagy. Of note, iPSCs (induced pluripotent stem cells) are a type of stem cell capable of generating almost any type of cell in the body.
Since compromised mitophagy could contribute substantially to AD, researchers tested whether boosting mitophagy in neurons could halt AD progression.
They performed a screen using the roundworm C. elegans to identify potent neuronal mitophagy inducers. They identified nicotinamide, already known to induce mitophagy, and two additional molecules (urolithin A and actinonin) as potent neuronal mitophagy-inducing agents.
Urolithin A is a natural metabolite found in pomegranate; actinonin is an antibiotic known to induce mitophagy in lab tests.
They then used a C. elegans model of AD that has the predominant form of amyloid beta, Aβ42, found in the brains of people with Alzheimer’s disease and investigated how boosting mitophagy influenced the animals’ memories.
The results showed that treatment with nicotinamide, urolithin A or actinonin improved the memory of the AD roundworms without affecting that of control (wild-type) animals.
To see whether the benefits would be preserved across other animals, they repeated the experiment using the APP/PS1 transgenic mouse model of AD. The animals were treated orally with urolithin A (200 mg/kg/day) or actinonin (30 mg/kg/day) for two months.
Molecular analysis showed that both compounds stimulated mitophagy and promoted the elimination of defective mitochondria in the hippocampus of the mice. Moreover, swimming tests showed that the treatment improved the animals’ learning and memory.
“It significantly strengthens our results that the cleaning process seems to be important in both human cells and across different animal species. And then it is encouraging that in living animals we are able to improve the central Alzheimer’s symptoms, memory and learning,” said Bohr.
Researchers then investigated the mechanism behind these benefits by comparing the gene expression in the hippocampus between control and AD mice with or without urolithin A. They saw that the treatment led to increased activity of genes linked with protection of neurons and memory.
“Our results suggest that mitophagy inhibits memory loss in AD mice through the maintenance of synapses in addition to neuronal function,” they wrote.
Moreover, boosting mitophagy with urolithin A promoted the activity of microglia, resident immune cells in the central nervous system (brain and spinal cord), which clear the Aβ plaques, the hallmark of AD. Treatment with urolithin A or actinonin also inhibits neuronal inflammation.
Overall, “our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis (disease development] and that mitophagy represents a potential therapeutic intervention,” researchers concluded.
They plan to start clinical trials for boosters of mitophagy in humans in the near future.
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