New research has revealed that the tau protein, which is important in the development of Alzheimer’s disease, is also involved in normal learning processes in the healthy brain, potentially providing a target for future drug therapies. Flinders University researchers discovered that the tau protein, whose role has long been unknown, may aid in molecular processes of memory formation in their study, which was published in The EMBO Journal.
The team used a sensitive method known as proximity labelling to identify all proteins that tau interacts with within brain cells, labeling and identifying the entire collection of interacting proteins as they went.
When the researchers examined the proteins that interact with tau and the specific functions that these interactions support, they discovered that while tau binds to proteins that support brain cell structure, it also interacts with proteins that control vesicles and cell surface receptors for neurotransmitters, both of which are required for learning and memory in the brain.
“Our new study took a snapshot of all partners tau engages with to support normal brain function,” says Dr. Arne Ittner, Senior Research Fellow in Neuroscience at the Flinders Health and Medical Research Institute and senior study author.
“Out of a wealth of partners, we identified one enzyme that critically controls neurotransmitter sensors. This enzyme, called NSF, is inhibited by tau, particularly in Alzheimer’s.”
Our new study took a snapshot of all partners tau engages with to support normal brain function. Out of a wealth of partners, we identified one enzyme that critically controls neurotransmitter sensors. This enzyme, called NSF, is inhibited by tau, particularly in Alzheimer’s.Dr. Arne Ittner
Changes in the connections between brain cells, called synapses, underly the processes involved in formation and retention of memory. These changes happen at the molecular level and help us store and retrieve memories, such as places visited or of loved ones.
When memories form, the number of neurotransmitter receptors – sensor molecules that detect messages from other brain cells – increase in synapses. This process is controlled by several factors, including an enzyme called ‘N-maleimide sensitive factor’, or simply NSF.
The new findings may be critical in our understanding of Alzheimer’s disease, the most common form of dementia. Alzheimer’s disease currently has no cure or effective therapy, in part due to gaps in our understanding of how the progressive neurodegenerative disorder arises in the brain. The tau protein is of central importance in Alzheimer’s disease and in half of all frontotemporal dementias.
While end-stages of Alzheimer’s have been known to neuropathologists for over a century, less well-known were how normal functions of tau may link to memory impairment at other stages in life. The new study identifies one such ‘starting point’ where things can begin to go wrong.
“We’re quite aware of the effects of tau protein in dementia-related memory loss but what is interesting to see is that tau helps control normal memory processes,” says study lead author and Flinders University PhD student Emmanuel Prikas.
After identifying NSF as a new partner of tau, the team focused on how tau specifically contributes to processes involving receptors for the neurotransmitter glutamate, using high-powered microscopic techniques and memory testing in mice.
Working with colleagues from Macquarie University to confirm how tau impacted NSF in cultured brain cells, the researchers saw that NSF was uncontrolled in cells lacking the tau protein, leading to abnormal behaviour of glutamate receptors.
“By removing and reintroducing the tau protein in brain cells, we were able to attribute changes in receptor behavior to tau changes, which may become focal points for future drug therapies,” Dr. Ittner says.
Importantly, the neurotransmitters glutamate and tau have previously been linked to seizures and stroke. As a result, the new findings establish a molecular link between tau’s normal function in controlling glutamate receptors in the brain and conditions of increased brain activity.
“Intriguingly, mutations in NSF have been linked to hereditary forms of epilepsy, putting this new discovery in close proximity to tau’s function in epilepsy and stroke,” Dr Ittner says.