Targeting a mitochondrial response to abnormal tau reduced brain-cell loss and memory problems in mice. Digest
Tau is a protein abundant in nerve cells, and its abnormal forms are linked to brain deterioration in Alzheimer's disease and other neurological conditions. Researchers investigated how tau affects mitochondria, the cell's energy-producing structures, and whether interrupting that interaction could protect neurons.
The study combined animal models, human neurons grown from stem cells, and brain tissue collected after death from people with and without tau-related disorders, including Alzheimer's disease. In animal and cell experiments, researchers altered tau and examined whether reverse electron transport, a backward flow of electrons in mitochondria, might contribute to tau-related mitochondrial dysfunction. To test this, they used CPT-2008, or CPT, an experimental compound that inhibits reverse electron transport.
- Reverse electron transport was elevated in mitochondria from tau-mutant human neurons and mice, and from postmortem brain tissue affected by tau-related disease. Forward flow remained relatively unchanged.
- Human neurons carrying a tau mutation became more vulnerable under chemically induced stress, and CPT partly protected them. Survival was not clearly different from control neurons without added stress.
- Mice with a disease-associated tau mutation receiving CPT performed better on learning and memory tests and retained more brain tissue and neurons than inactive-treatment controls.
- CPT also reduced neuron loss, improved movement, learning, and memory, and extended lifespan in adult flies with a disease-associated tau mutation. A genetic method of inhibiting reverse electron transport produced similar behavioral and lifespan benefits.
Chemical modifications help determine how tau affects mitochondria. Adding phosphate groups at certain sites allowed tau to promote reverse electron flow, whereas preventing some of those additions blocked the effect. Modified tau could enter mitochondria and directly bind a component of complex I, the protein machinery that normally starts the forward transfer of electrons used in energy production. Changes in that machinery may favor backward flow, generating reactive oxygen molecules that can damage cells and disrupting the balance between NAD+ and NADH, two forms of an electron-carrying molecule. Those disturbances can encourage further phosphate additions to tau. This creates a possible self-reinforcing cycle in which altered tau disrupts mitochondria, and the resulting stress encourages more harmful changes to tau.
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Tau's effects appear to depend on its chemical modifications and cellular interactions, not only on the presence of the protein. That distinction creates room for strategies aimed at the processes that make tau harmful, rather than treating all tau as the same target.