Breakdowns in mitochondrial housekeeping provide another clue to Alzheimer's culprit

Researchers have zeroed in on the role of defects in mitophagy—a process in which cells clean out damaged or defective mitochondria—as a potential new treatment target for Alzheimer’s disease in experiments with animal models and lab specimens of human neurons. An international team of scientists led by NIA Intramural Research Program investigators in the Laboratory of Molecular Gerontology published their results in the March issue of Nature Neuroscience.

The brain is a high-octane machine, accounting for up to 25 percent of the body’s total energy consumption despite being only about two percent of body weight. Since mitochondria are the powerhouses of cells, a breakdown in mitophagy impairs neurons’ metabolism and makes them more vulnerable to cell dysfunction and death.

The scientific team wanted to better understand whether the large accumulations of damaged mitochondria found in post-mortem brain samples from people who had Alzheimer’s disease might be further evidence for mitophagy malfunctions as a major factor in the disease. Confirming their hypothesis, the research team also found significant amounts of damaged mitochondria in neuron samples from Alzheimer’s models in mice and in the worm C. elegans, indicating a dramatic reduction in mitophagy.

Next, the team worked to identify drug compounds that would stimulate and reinvigorate the mitophagy process, hoping to see improvements in dementia symptoms and pathology. They found three promising candidates: nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide NAD+, which is crucial for cellular energy metabolism; Urolithin A, a compound found in pomegranate that induces muscular mitophagy; and Actinonin, a naturally occurring antibacterial agent.

Alzheimer’s mice treated with these compounds performed much better in memory tests and showed reduced neuroinflammation and lower accumulation of amyloid-beta and phosphorylated tau in their brains. The compounds also improved the quality of neurons generated from induced pluripotent stem cells (iPSC) grown from skin cell samples of people with Alzheimer’s disease.

These results point to mitophagy’s importance in the development and progression of Alzheimer’s disease and help open doors for potential drug development into mitophagy regulators as an intervention for Alzheimer’s.

Additionally, investigators believe their unique cross-species drug development platform—encompassing C. elegans, mice, and Alzheimer's disease patient iPSC-derived neurons—can increase the likelihood of finding robust drug candidates for Alzheimer’s disease clinical trials.

References:

Fang EF, et al. Mitophagy inhibits Aβ and p-Tau pathologies and cognitive deficits in experimental models of Alzheimer’s disease. Nature Neuroscience. 2019;22(3):401-412.

Kingwell K. Turning up mitophagy in Alzheimer disease. Nature Reviews Drug Discovery. Published online March 4, 2019.