Targeting Tau to keep neurons connected
An international team of researchers led by Patrik Verstreken at VIB-KU Leuven has succeeded in reversing the effects of Tau, a protein implicated in over 20 different diseases, including Alzheimer’s disease. The promising findings in animal models are an important first step in the exploration of a new therapeutic avenue targeting cognitive decline.
The Tau protein is implicated in numerous neurodegenerative disorders, sometimes called ‘tauopathies’, including Alzheimer’s disease and other types of dementia. In all these diseases, Tau causes havoc by aggregating within neurons. While such Tau aggregates are closely correlated with cognitive decline, we still don’t fully understand how they cause it.
“In tauopathies, we observe inflammation and loss of neuronal connections in the brain, even before Tau aggregates start to form on a massive scale,” says Patrik Verstreken, head of the VIB-KU Leuven Center for Brain & Disease Research. Verstreken and his team are specialized in neuronal communication and its links to disease. They teamed up with colleagues at the UK Dementia Research Institute to explore how the different aspects of the disease process lead to the cognitive symptoms induced by Tau.
Partner in crime
The team turned their attention to another neuronal protein: Synaptogyrin-3. It is one of the proteins Tau interacts with, but it can only be found in the vicinity of neuronal connections, explains Pablo Largo-Barrientos, PhD student in the Verstreken lab: “Since Synaptogyrin-3 is only present near neuronal connections, we interfered with its function to determine the role Tau plays specifically at this location.”
By eliminating Tau’s partner in crime in a mouse model, the researchers could prevent the loss of neuronal connections that Tau would normally induce. “We also found that the working memory of these mice didn’t decline as we’d normally expect,” adds Largo-Barrientos.
Intriguingly, however, the inflammation effects remained the same. This led the researchers to propose that Tau induces inflammatory effects and loss of connectivity independently, and that the latter is a major determinant of cognitive decline.
A window of opportunity
“Our work provides the first evidence that it is possible to rescue the loss of neuronal connections and memory impairment, namely by targeting Tau specifically where neurons connect,” says Verstreken.
The researchers are now developing drugs that could decrease Synaptogyrin-3 levels in the brain. With those, they plan to test the therapeutic value of this approach for tauopathies, eventually in patients.
(Source: press release VIB)