Tau tangles brains

As if Alzheimer’s wasn’t vicious enough, researchers have found the wrong type of breakthrough – a brutal process where toxic proteins break through membranes and leak into neurons.

A team led by Jürgen Götz and Juan Polanco from the University of Queensland found that entanglements in neurons – a common sign of dementia – are formed partly because of a faulty cellular process that allows a toxic protein, called tau, to leak into healthy brain cells. 

“These leaks create a damaging seeding process that causes tau tangles and ultimately leads to memory loss and other impairments,” says Götz. 

Normally, tau protein helps form and stabilise microtubules that help the cell cytoskeleton keep its shape. Mutant tau doesn’t bind to the microtubule properly and forms a “seed” that forces other tau to misfold and aggregate in an insoluble mess called a neurofibrillary tangle.

Until now, it was unclear how the tau seeds were able to escape from cells to implant themselves and corrupt other cells.

“In people with Alzheimer’s disease, it seems the tiny sacs transporting messages within or outside the cells, called exosomes, trigger a reaction which punches holes in the wall of their own cell membrane and allows the toxic seeds to escape,” says Götz.

“As more tau builds up in the brain, it eventually forms tangles, and together with abnormally configured proteins known asamyloid plaque, they form the key features of these neurological diseases.”

To add to the brutality, the team found that the exosomes were able to increase the spread of seeds by hijacking the pathway of endosomes, the “vehicles” that travel and transport messages inside the cell to the lysosome – a cell organelle that uses enzymes to digest worn-out cell parts.

In their paper, published in the journal Acta Neuropathologica, the researchers show that the enzyme activity of lysosomes appears to make exosomes membranes more permeable, which allows the tau proteins to viscerally drill through and escape to wreak havoc. 

“Improving our understanding of how Alzheimer’s and other diseases spread through exosomes will allow us to create new ways to treat and intervene in these cellular processes in the future,” says Polanco. “The more we understand the underlying mechanisms, the easier it will be to interfere with the process and to slow down or even halt the disease.”

For example, this biochemical mechanism may provide insight into how and why non-inherited forms of Alzheimer’s and other dementias occur.

“Along with Alzheimer’s, this cellular process might also play a leading role in other cognitive diseases, from frontal lobe dementia to rare neurological disorders with toxic tau,” says Polanco.

“Even in cancer research, there is emerging evidence showing these exosomes can load unique messages that reflect the condition of tumours and enables them to replicate and spread cancer more quickly through the body.”

The research was conducted in mouse models.