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New understanding of impact of tau in neurodegenerative disease

Research reveals the physical damage the protein can cause to neurons within the brain

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Researchers have discovered how harmful tau proteins damage the operation of brain cells in neurodegenerative diseases – a finding which could lead to new treatments and interventions. 

The toxic protein was found to warp the shape of the neurons in a person’s brain, which alters the function of genes contained inside and reprogrammes the cells to make more tau. 

This research, from the University of Virginia (UVA), confirms the physical harm that tau cases to neurons – helping to shed new light on potential new treatments for conditions like Alzheimer’s disease and chronic traumatic encephalopathy (CTE) where currently there are none. 

“A lot of fantastic research has been done by other labs to learn how toxic tau spreads from neuron to neuron in the brain, but very little is known about exactly how this toxic tau damages neurons, and that question is the motivation for our new paper,” said Dr George Bloom, of the UVA Brain Institute, the Virginia Alzheimer’s Disease Center and UVA’s Program in Fundamental Neuroscience. 

“The toxic tau described here is actually released from neurons, so if we can figure out how to intercept it when it’s floating around in the brain outside of neurons, using antibodies or other drugs, it might be possible to slow or halt progression of Alzheimer’s disease and other tauopathies.”

Tauopathies are characterised by the build-up of tau inside the brain. Alzheimer’s disease is well known, but there are many other tauopathies, including frontotemporal lobar degeneration, progressive supranuclear palsy and CTE. 

These diseases typically present as dementia, personality changes and/or movement problems. There are no treatments available for non-Alzheimer’s tauopathies, so the UVA researchers were eager to better understand what is happening, so that scientists can find ways to prevent or treat it.

Dr Bloom and his team discovered that tau ‘oligomers’ – assemblages of multiple tau proteins – can have dramatic effects on the normally smooth shape of neuronal nuclei. The oligomers cause the nuclei to fold in on themselves, or “invaginate,” disrupting the genetic material contained within. 

The physical location and arrangement of genes affects how they work, so this unnatural rearrangement can have dire effects.

“Our discovery that tau oligomers alter the shape of the nucleus drove us to the next step – testing the idea that changes in gene expression are caused by the nuclear shape change,” Dr Bloom said. 

“That’s exactly what we saw for many genes, and the biggest change is that the gene for tau itself increases its expression almost three-fold. So bad tau might cause more bad tau to be made by neurons – that would be like a snowball rolling downhill.”

The researchers found that patients with Alzheimer’s disease had twice as many invaginated nuclei as people without the condition. Increases were also seen in lab mice used as models of Alzheimer’s and another tauopathy.

The researchers say that additional research into how this process happens could open the door to new ways to prevent and treat Alzheimer’s and other tauopathies.

 

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