How the brain changes in Alzheimer’s Disease: a new view

TheConversation: 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.

So common, still no cure

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.

Changes to proteins cause brain cell death

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.

Light micrograph of brain tissue stained with a silver impregnation. A plaque (upper centre) and a pyramid-shaped neuron with a tangle (lower left) can be seen. Both lesions are typical in Alzheimer’s disease. from www.shutterstock.com

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.

Unexpected protection against Alzheimer’s Disease

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.

New target for prevention and treatment

These findings have implications for prevention and treatment of Alzheimer’s disease.
When we increased levels of protective tau, dementia-like memory changes were largely prevented in mice predisposed to developing Alzheimer’s. The next question is to see whether this specific tau modification can act in a protective way at even later stages of disease.
Further exploration may result in a new treatment approach that involves increasing the activity of the gene linked to forming protective tau at an advanced stage of Alzheimer’s. This is important as many patients are diagnosed with dementia when considerable memory and neuronal loss has already occurred.
We consider there are two approaches to increase protective tau. One of them uses vehicles for gene delivery, while the other aims to develop drugs that can increase formation. Our team is planning to follow both strategies as we move towards the development of possible new treatments for humans.
Considering the multitude of possible modifications of tau protein that exist, dissecting the functions of each of these does seem a tedious task to many. However, it may yet reveal other remarkable insights into dementia and lead us to new treatment strategies that are so urgently needed.