Most people have heard of Alzheimer’s disease, the most common form of dementia. The disease has no cure and few, but inefficient, treatments. Despite their best efforts, doctors and researchers still don’t know the sequence of brain changes that causes this debilitating disorder.
Our new study challenges a commonly held view of how Alzheimer’s disease develops, and suggests a new clinical angle to reduce its impact.
Alzheimer’s disease is the most common form of dementia, characterised by progressive loss of cognition – our ability to learn, remember and plan our lives. Over 35 million people are currently diagnosed with Alzheimer’s disease worldwide, with figures set to increase significantly due to an ageing population.
Unfortunately, we have no cure and current therapies are limited to very modest symptomatic relief. Therefore, there is a great need for understanding how Alzheimer’s disease develops, and what the underlying processes are in order to develop effective treatments.
After death, the brains of Alzheimer’s disease patients are typically found to contain two types of abnormal structures when viewed under the microscope: plaques and tangles. Plaques contain a protein known as amyloid beta, and tangles consist of a protein called tau.
Tau is a protein that normally resides within brain cells (also called neurons). However, tau in Alzheimer’s disease brain tangles is not the same as tau in normal brains.
Tau in tangles has a unique structure, and is called phosphorylated because it carries extra molecules known as phosphates attached to the main protein backbone. This changes the way the protein behaves inside the neuron.
The prevailing belief in Alzheimer’s disease research is the addition of phosphate groups to create phosphorylated tau promotes disease development.
Our recent research challenges this assumption.
We recently uncovered a new and surprising clue as to the role of tau and phosphates in Alzheimer’s.
Our first piece of evidence came from looking at genes. We found a gene that unexpectedly protected mice against developing Alzheimer’s. We also saw that levels of the protein that results from this gene gradually decrease in the human brain as Alzheimer’s progresses.
Using a combination of experiments in cultured mouse neurons, we then studied exactly how this gene works. It became clear the gene influences the way phosphate groups are attached to tau. By creating a specific pattern of phosphorylation of tau, the gene mediated its protective effects.
We also found when mice were given tau with this specific pattern of attached phosphate groups, they were protected from developing Alzheimer’s disease.
This research led us to change our thinking about the molecular events that occur in Alzheimer’s disease.
We found a specific pattern of tau phosphorylation can protect against death of neurons in a mouse model of the disease. In other words, a version of phosphorylated tau that is protective against Alzheimer’s disease can form in the brain. This challenges the common view among researchers that tau phosphorylation only causes toxic effects and is the “villain” in disease progression.