Alzheimer's scientists uncover "seeding" process of toxic protein tangles

Alzheimer's scientists uncover...
Tau tangles (blue) can build up inside neurons, and are implicated in the formation of Alzheimer's
Tau tangles (blue) can build up inside neurons, and are implicated in the formation of Alzheimer's
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Tau tangles (blue) can build up inside neurons, and are implicated in the formation of Alzheimer's
Tau tangles (blue) can build up inside neurons, and are implicated in the formation of Alzheimer's

Researchers in Australia and China have shed new light on the murky origins of neurodegenerative diseases like Alzheimer’s, which could eventually lead to new treatments. The team uncovered a mechanism for how toxic tangles of tau proteins leak into healthy brain cells.

In a normal, healthy brain, tau proteins are vital for stabilizing microtubules, which provide structure to cells and help transport nutrients. But sometimes, these proteins can misfold and begin to clump together into abnormal structures called neurofibrillary tangles. Because these tangles appear in higher numbers in patients with Alzheimer’s and other neurodegenerative diseases, they remain a key suspect in the hunt for the root cause of these conditions.

But exactly how they spread between neurons has remained unclear. Now, researchers from the University of Queensland in Australia and Huazhong University of Science and Technology in China claim to have found how the tangles leak into healthy cells.

In previous work, the team found that tau “seeds” start off encapsulated in exosomes, tiny “messenger” sacs inside cells that contain things like proteins and DNA. They found that exosomes could jump across synapses to neighboring neurons, and on arrival induce tau protein clumps. But how the tau seeds were escaping from the exosomes was unknown.

In the new study, the researchers discovered the process responsible. The key, it turns out, is the lysosome, a cell structure that uses digestive enzymes to break down proteins when they’re faulty or no longer needed. The tau seeds appear to hijack this function and use it to make the exosomes more permeable, allowing them to escape into the fluid of the cell and begin building up.

“In people with Alzheimer’s disease, it seems the … exosomes trigger a reaction which punches holes in the wall of their own cell membrane and allows the toxic seeds to escape,” says Jürgen Götz, lead author of the study. “These leaks create a damaging seeding process that causes tau tangles and ultimately lead to memory loss and other impairments.”

Identifying this mechanism could potentially pave the way for new treatments for these neurodegenerative diseases. And the researchers have already investigated some of the possible techniques to do so. They found that a protein called RAB7 is linked to tau tangles – overexpression increased the amount of tau buildup, while knocking it down reduced it. The team also found that inhibiting lysosome function decreased tau aggregation.

"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," says Juan Polanco, an author of the study.

"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. 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.”

The research was published in the journal Acta Neuropathologica.

Source: University of Queensland

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