Research collaboration changes understanding of Alzheimer’s disease

The mechanism unexpectedly drives neurons to enter a regenerative state, which protects the cells from the toxicity of Alzheimer’s disease-causing plaque proteins.

Their finding, which was published in the Proceedings of the National Academy of Sciences of the USA, has upended a long-standing theory about what happens in the brain to cause Alzheimer’s disease.

Alzheimer's disease is the most common form of dementia and Australia's second leading cause of death.

Macquarie’s Dementia Research Centre Director, Professor Lars Ittner, says that up until now the exact opposite was believed to be the case, and that these unusual neurons were thought to be more likely to succumb to toxins.

“Basically we have thrown a long-standing theory of how Alzheimer’s disease comes about overboard, and opened up new research opportunities to better understand the disease in the first place, but also in the long-term to intervene and capitalise on these processes in order to protect neurons,” says Professor Ittner.

Many years ago, Ittner says, scientists had observed that neurons in the brains of sufferers of AD – the most common form of dementia – had started to re-enter the cell-cycle process, in which cells through a series of events divide into two.

This was significant because neurons are not meant to multiply and recover lost numbers. They are ‘post-mitotic’ cells, which, unlike the cells in other organs of the body, do not regenerate.

“We all know that in Alzheimer’s disease we are losing brain cells, called neurons, and it was thought for a long time that the neurons we are born with are all that we will ever have, so if you lose a neuron it, and the information it has stored, are gone forever.”

When the re-activated neurons were observed in post-mortem Alzheimer’s disease brains, the theory was put forward that these neurons were more vulnerable to toxins such as oligomeric amyloid-beta – the plaque protein causing Alzheimer’s disease.

“This was the scene where our work started,” says Ittner.

“We found that the observation was not in line with the theory, because when an Alzheimer’s disease brain comes for autopsy there are more of these neurons that are in a cell-cycle stage, and we asked why aren’t there less of them because if they are more vulnerable they should be gone.”

Collaboration the key to breakthrough

Ittner’s team partnered with his friend and cancer researcher Professor Nikolas Haass, from The University of Queensland. Professor Haas applies ground-breaking technology to study the life cycle of cells for his research into melanoma and drug resistance.

Using red and green fluorescent markers, Haass’s technique allows researchers to visualise under the microscope the events of the cell cycle, and cell death.

“We employed this tool to neurons, and then exposed them to the beta-amyloid toxin found in the Alzheimer’s disease brain,” says Ittner.

“What we observed is that there were indeed cells that entered the cell cycle, but contrary to the opinion that they are more vulnerable, they in fact survived longer while the neurons that failed to activate the cell cycle, underwent cell death.”

The researchers observed the same results first in cultures of neurons, and then in the brains of mice genetically engineered to develop Alzheimer’s disease.

Professor Haass says, “This new paper nicely demonstrates that methodologies developed for research in to one disease (cancer) can be extended to address other interdisciplinary entities, such as Alzheimer’s disease.

“Our findings are very exciting, as we challenge one of the long-standing theories for how Alzheimer’s disease develops.”

Ittner says: “The next step for us is to interfere in the processes we have observed in order to find ways to activate the protective effects of neurons.”

This article was first published by Macquarie University