Toxic Tau Aggregates Alter Cell Nucleus Structure in Harmful Ways
The set of neurodegenerative diseases characterized by aggregation of altered tau protein are collectively known as tauopathies. Alzheimer's disease is the best known of these conditions. The later stage of Alzheimer's disease, in which cell death is widespread, is characterized by tau aggregation and chronic inflammation of brain tissue. As noted here, how exactly tau alteration and aggregation causes dysfunction is still an active area of research that may result in ways to sabotage the progression of tauopathies.
Tauopathies are characterized by the buildup 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 chronic traumatic encephalopathy. These diseases typically present as dementia, personality changes and/or movement problems. "A lot of fantastic research has been done 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. 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."
Researchers 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. 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.