Look deep inside the brain of someone with Alzheimer's disease, most forms of dementia or the concussion-related syndrome known as chronic traumatic encephalopathy (CTE) and you'll find a common suspected culprit: stringy, hairball-like tangles of a protein called tau.

Such conditions, collectively known as "tauopathies" strike scores of people across the globe, with Alzheimer's alone affecting six million people in the United States.

But more than a century after German psychiatrist Alois Alzheimer discovered tau tangles, scientists still have much to learn about them.

A study published in the journal Neuron, shows for the first time that tau aggregates gobble up RNA, or ribonucleic acid, inside cells and interfere with an integral mechanism called splicing, by which cells ultimately produce needed proteins.

"Understanding how tau leads to neurodegeneration is the crux of not just understanding Alzheimer's disease but also multiple other neurological diseases," said the senior author. "If we can understand what it does and how it goes bad in disease we can develop new therapies for conditions that now are largely untreatable."

"There is nothing we can do for these patients right now - no disease modifying-treatments for Alzheimer's or most of the other tauopathies," the lead author said, noting that 70% of neurodegenerative diseases are believed to be at least partially related to tau aggregates.

For the study, the researchers isolated tau aggregates from cell lines and from the brains of mice with an Alzheimer's-like condition. Then they used genetic sequencing techniques to determine what was inside.

They confirmed for the first time that tau aggregates contain RNA, or ribonucleic acid, a single-stranded molecule key for synthesizing proteins in cells. They identified what kind of RNA it is, specifically snRNA, or small nuclear RNA, and snoRNA, or small nucleolar RNA.

They also discovered that tau interacts with pieces of cellular machinery known as nuclear speckles, sequestering and displacing proteins inside them and disrupting a process called RNA splicing in which the cell weeds out unneeded material to generate new, healthy RNA.

The authors observed several nuclear speckle components, including SRRM2, mislocalize to cytosolic tau aggregates in cells, mouse brains, and brains of individuals with AD, frontotemporal dementia (FTD), and corticobasal degeneration (CBD). Consistent with these alterations, they saw the presence of tau aggregates is sufficient to alter pre-mRNA splicing.

"The tau aggregates appear to be sequestering splicing-related RNA and proteins, disrupting their normal function and impairing the cell's ability to make proteins," said the senior author.

Notably, scientists examining the brains of Alzheimer's patients after death have discovered evidence of splicing-related defects in cells.

The paper is the first in a series out of the lab to explore the mechanism of action by which tau aggregates gum up the works inside brain cells.

Already, several companies have clinical trials underway testing drugs that would do away with tau entirely in patients with neurodegenerative diseases. But that could potentially have unintended consequences, said the senior author.

"A big problem in the field is that no one really knows what tau does in healthy people and It likely has important functions when not in tangles," the author said.

By better understanding precisely what it does to harm and kill cells, the authors hope to bring a different approach to the table.

"The idea would be to intervene in the abnormal functions while preserving the normal functions of tau," the senior author said.

https://www.colorado.edu/today/2021/04/15/how-tangled-protein-kills-brain-cells-promotes-alzheimers

https://www.cell.com/neuron/fulltext/S0896-6273(21)00196-3