Elevated calcium in mitochondria linked to cell death in Alzheimer's
There are many unknowns when it comes to the complex mechanisms underpinning Alzheimer's disease, but research is continuing to shine a light on some of the key suspects. A new mouse study from Massachusetts General Hospital has for the first time established a connection between elevated levels of calcium in mitochondria and neuron death associated with the disease, offering a potential new target for efforts to slow its progression.
The new research builds on studies that had pointed to a relationship between calcium levels in mitochondria and neuronal death, as observed in cell culture. This ties in with one of the prevailing hypotheses on the causes of Alzheimer's, namely, the aggregation of amyloid beta plaques in the brain, which are toxic clumps of proteins thought to systematically destroy neurons.
While the jury is still out on the amyloid beta hypothesis, with many drugs targeting the mechanism failing in major clinical trials, it remains an area of focus for many researchers in the field. The scientists behind the new study set out to explore how calcium levels might be a thread that connects amyloid beta with neuronal death, with the plaques known to cause high levels of calcium ions in brain cells in culture.
Cell culture studies had also uncovered evidence that exposure to amyloid beta plaques can drive up calcium ion levels in mitochondria, the powerhouses of cells, and cause neurons to die off. This occurs through what is known as the “mitochondrial calcium uniporter,” which drives uptake of calcium ions into the mitochondria, though until now scientists haven't had technologies sophisticated enough to study this mechanism in living mouse models of Alzheimer's disease.
To do so, the scientists turned to an advanced imaging technique called multiphoton-micropscopy, and combined it with special fluorescent dyes that target the mitochondria. This revealed a clear link between elevated levels of calcium ions in the mitochondria, plaque aggregation and neuronal death in the living brain.
While there is a long way to go before these results could be translated from mice to people, and then even longer before a safe and effective therapy is developed that targets this mechanism in human patients, the team is optimistic about the possibilities.
Post-mortem analysis of Alzheimer's patient's brains has shown an association between gene expression and regulation of calcium ions in the mitochondria, seemingly as a way to keep levels balanced. The team also conducted experiments where a form of amyloid-beta was administered to healthy mouse brains, and was found to drive up concentrations of calcium ions in the mitochondria. The researchers believe it could be possible to intervene in this process with drugs that block the mitochondrial calcium uniporter.
“High calcium levels in the mitochondria cause oxidative stress, and the death of neurons via apoptosis,” says lead author of the paper, Maria Calvo-Rodriguez. “We propose that by blocking the neuronal mitochondrial calcium uniporter we can prevent cell death and impact disease progression.”
The research was published in the journal Nature Communications.
Source: Massachusetts General Hospital