Scientists may have discovered one reason the brain damage associated with Alzheimer’s disease can keep getting worse once it starts.
The research centers on tau, a protein that normally helps brain cells function but can become abnormal and form the tangles associated with Alzheimer’s and several other brain diseases.
Researchers found evidence of a troubling cycle inside brain cells. Abnormal tau appears to interfere with mitochondria—the structures that help provide cells with energy. But instead of the damage stopping there, the affected mitochondria appear to trigger changes that make even more tau abnormal. In other words, one problem may help fuel the other.
When researchers interrupted that cycle in laboratory and animal experiments, some of the tau-related damage decreased. That raises the possibility of a new target for future treatments.
There is an important caveat: this is early-stage research, not a new Alzheimer’s treatment. The work involved animal models, human brain tissue and human nerve cells grown in the laboratory, not a clinical trial in people. But it may give scientists another clue about how Alzheimer’s-related damage progresses—and potentially where that cycle could someday be interrupted.
When Tau goes wrong
Tau is a protein that normally helps brain cells stay healthy and function properly. But in Alzheimer’s disease and some other brain disorders, tau can change in harmful ways and eventually form the tangles found in affected brains.
Scientists have known for years that abnormal tau often appears alongside problems with mitochondria, the structures that help provide brain cells with energy. What they haven’t fully understood is whether one problem helps cause the other.
The new research suggests they may actually make each other worse, creating a damaging cycle. If scientists can figure out where to interrupt that cycle, it could eventually point to new ways to slow the damage.
The mitochondria started running part of their machinery backward
The NIH-funded study, published in Neuron and summarized by the National Institutes of Health, focused on reverse electron transport. Mitochondria normally move electrons through a chain of proteins to help produce cellular energy; under certain conditions, electrons can flow in the reverse direction.
Researchers found that hyperphosphorylated tau promoted this reverse flow. Reverse electron transport then activated enzymes that added still more phosphate groups to tau, potentially creating a self-reinforcing cycle.
Mitochondria do far more than act as cellular batteries. They help regulate metabolism, stress responses and cell survival, which means mitochondrial dysfunction can ripple through a neuron in several ways. Neurons are especially dependent on reliable energy production because their long projections and constant electrical signaling are energetically expensive.
Abnormal tau may not simply damage mitochondria once; mitochondrial dysfunction may feed back and make the tau abnormality worse.
Blocking the loop reduced damage in experimental models
When researchers interfered with reverse electron transport in experimental systems, they saw reductions in tau-related problems and neurodegeneration. That makes the mitochondrial pathway interesting as a potential therapeutic target.
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But the experiments spanned flies, mice, cultured cells and human tissue rather than a clinical trial in people with Alzheimer’s disease. A drug that changes mitochondrial electron flow would also need careful safety testing because mitochondria are essential to healthy cells throughout the body.
A target can look powerful in a disease model and still prove too risky, too difficult to reach or insufficiently effective in patients.
This could matter beyond Alzheimer’s disease
Tau pathology occurs in several neurodegenerative disorders, including some forms of frontotemporal dementia. If the same mitochondrial feedback loop contributes across tauopathies, the mechanism could have implications beyond a single diagnosis.
Researchers will need to establish when the loop begins during disease, whether it drives progression in human brains and whether interrupting it after symptoms appear is still beneficial.
The timing question is crucial: stopping a feedback loop early may be very different from trying to reverse years of accumulated neuronal damage.
Final word
Scientists are still trying to understand exactly how Alzheimer’s damages the brain and why that damage gets worse over time. This study offers a new clue.
The researchers found evidence that abnormal tau and problems with the parts of brain cells that produce energy may feed off each other, creating a cycle that causes more damage.
This discovery is not a cure or a new treatment. But if scientists can find a safe way to interrupt that cycle, it could eventually lead to another approach for slowing the disease.
