Tangled Up in Tau
But for all of the non-Alzheimer’s tauopathies, the spotlight is on tau. Tau is a soluble protein that normally binds tightly to MTs and rarely clumps up. The problem comes when excessive and abnormal phosphate groups attach to the protein, causing it to loosen from the MTs and leading to accumulation of tau inside the neuron. Those filaments of tau, now insoluble, attract other proteins, filling the neuron and eventually leading to death of the neuron. Meanwhile, lacking tau to stabilize them, the MTs unravel and the cell’s transport system begins to fall apart. “The cell doesn’t get its energy at the proper places at the right time, and the synapses start decaying,” says longtime tau researcher Eckhard Mandelkow of the Max Planck Institute in Hamburg and the German Center for Neurodegenerative Diseases in Bonn. With the synapses impaired, the neuron stops functioning and dies.
Where the tau tangles occur and what type of neurons they affect determine the symptoms of individual tauopathies. Tau deposits in the cerebral cortex are characteristic of FTD, with symptoms of impulsivity, poor judgment and obsessive behavior. In people who have progressive supranuclear palsy, both neurons and support cells called astrocytes are affected in the brain stem and basal ganglia, causing rapidly progressing and disabling Parkinsonism and eye movement abnormalities. Tau in other brain regions, however, causes corticobasal degeneration. Different strains of tau appear to prefer certain brain regions and specific types of neurons.
Pathologists have long known that tau pathology spreads through the brain one region at a time. But how that occurs wasn’t understood until recent mouse studies and cell culture experiments showed that abnormal tau escapes one neuron and is taken up by neighboring cells, a phenomenon not normally seen in cells. “Maybe tau has a tendency to aggregate in brain cells normally, but the healthy brain can get rid of it,” says Goedert. “And the younger you are, the better that works.”
When a tangle doesn’t dissolve, a few particles break out of the cell membrane and into the spaces between neurons, giving tau an opportunity to infiltrate neighboring cells and generate a new tangle. The greater the number of tau aggregates in the brain, the worse the symptoms of dementia. Further proof that tau can leak out of neurons is that the protein shows up in cerebral spinal fluid—a phenomenon that might provide a way to diagnose tauopathies before symptoms appear.