Researchers at the University of Queensland Brain Institute (St Lucia, Australia) used superresolution microscopy to observe key molecules at work inside living brain cells, helping to uncover memory formation and the elusive causes of dementia.
Frédéric Meunier and Jürgen Götz, both professors at the University of Queensland Brain Institute's Clem Jones Centre for Ageing and Dementia Research, found that the Tau protein involved in Alzheimer's disease affects the organization of the signaling protein Fyn, which plays a critical role in memory formation.
"One of the distinguishing features of Alzheimer's disease is the tangles of Tau protein that form inside brain cells, but this is the first time anyone has demonstrated that Fyn nanoclustering is affected by Tau," Götz says.
Meunier says that single-molecule imaging in living brain cells allowed unprecedented access to the organization of key proteins in small nanoclusters that were not detectable previously. "We have shown that Tau controls the Fyn nanoclustering in dendrites, where the communication between brain cells occurs," he explains. "When Tau is mutated, Fyn makes aberrantly large clusters, thereby altering nerve signals and contributing to dysfunction of the synapse-junctions between nerve cells."
Meunier's team used the superresolution single-molecule imaging technique to see how Tau and its mutants control Fyn nanoclustering. Meunier went on to investigate a different mutant of Tau found in families with a very high risk of developing frontotemporal dementia and found that Fyn was overclustered in the spines of dendrites.
"Imagine that you have clustering of Fyn, a signaling molecule, throughout your life; it's going to give rise to an over-signaling problem—this could be one of the ways in which Fyn is toxic to cells," Meunier says. "The spines of the dendrites are critical to how nerve cells communicate with each other and underpin memory and learning," he adds.
Exactly what causes Alzheimer's and other forms of dementia is still a mystery, but Fyn is linked to both the plaques of amyloid protein that form between brain cells, and tangles of Tau protein that form inside brain cells—two distinguishing features of Alzheimer's disease.
"Superresolution single-molecule imaging gives us an unprecedented insights into what is happening in living nerve cells, with the aim of understanding the biology behind these complex and debilitating diseases," Meunier says.
Full details of the work appear in the journal eLife.