Many research groups have published evidence to suggest that age-related mitochondrial dysfunction is an important aspect of neurodegenerative conditions such as Alzheimer's disease. The brain is an energy-hungry organ and mitochondria are the power plants of the cell, responsible for producing the chemical energy store molecules that power cellular activity. It is well known that mitochondrial function declines with age; mitochondria in old tissues are structurally different, and less effective at their jobs.
The research results here suggest that this mitochondrial decline has a lot to do with the fact that the cellular housekeeping processes of autophagy falter with age, and in particular mitophagy, the autophagic recycling of damaged or dysfunctional mitochondria. The degree of benefit seen from boosted mitophagy indicates that perhaps it is higher rather than lower in the hierarchy of mechanisms. That said, there is good evidence from other studies for lapsed mitophagy to be a consequence of deeper changes in mitochondrial dynamics that make it harder for the autophagic processes to operate. The question of the best place to intervene is probably one best settled by trying the various potential approaches in order to see how well they work.
A point worth noting, as for all Alzheimer's research, is that the animal models of this condition are highly artificial. Old mice do not normally undergoing anything even remotely akin to the processes underlying Alzheimer's disease, and thus there is always the question of whether or not the results in a mouse model have anything to do with the way in which the condition proceeds in humans. One can be reasonable confident that mitochondrial dysfunction is similar between mammalian species, based on the past few decades of research, but it is the linkage of that dysfunction to either Alzheimer's or the faux-Alzheimer's of the model that is the thorny point. I do think it reasonable to believe that improved autophagy (in general) or mitophagy (in specific) will produce some degree of benefits across the board in human cellular biochemistry - but will the benefits for Alzheimer's patients be of the same order as those observed in mice?
Researchers have come closer to a new way of attacking Alzheimer's disease. They target the efforts towards the cleaning process in the brain cells called mitophagy. "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."
The researchers have looked more closely at mitophagy in brain cells from deceased Alzheimer's patients, in Alzheimer's-induced stem cells and in live mice and roundworms with Alzheimer's. In addition, they have also tested active substances targeted at mitophagy in the animal models. The mitochondria lie inside the cell and can be seen as the cell's energy factories. Mitophagy breaks down defective mitochondria and reuses the proteins that they consist of. It is known from previous research that dysfunctional mitophagy is associated with poor function and survival of nerve cells, but so far, the connection with Alzheimer's is unclear.
In both Alzheimer's and other states of dementia, there is an accumulation of the proteins tau and beta amyloid in the brain, leading to cell death. In the new animal models, the researchers show that when boosting the mitophagy, such accumulation will slow down. The researchers believe that altogether their findings indicate that mitophagy is a potential target for the treatment of Alzheimer's, which should be further investigated. They therefore plan to start clinical trials in humans in the near future.
Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegeneration, including Alzheimer's disease (AD). The molecular mechanisms of impaired mitochondrial homeostasis in AD are being investigated. Here we provide evidence that mitophagy is impaired in the hippocampus of AD patients, in induced pluripotent stem cell-derived human AD neurons, and in animal AD models.
In both amyloid-β (Aβ) and tau Caenorhabditis elegans models of AD, mitophagy stimulation (through NAD+ supplementation, urolithin A, and actinonin) reverses memory impairment through PINK-1, PDR-1, or DCT-1 dependent pathways. Mitophagy diminishes insoluble Aβ1-42 and Aβ1-40 and prevents cognitive impairment in an APP/PS1 mouse model through microglial phagocytosis of extracellular Aβ plaques and suppression of neuroinflammation. Mitophagy enhancement abolishes AD-related tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic tau nematodes and mice. Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention.