How Tau Pathology May Spread in the Alzheimer's Brain

Neurofibrillary tangles are a hallmark of Alzheimer's disease. Tangles are composed of misfolded forms of the protein tau-a structural change that results in tau clumping into insoluble fibrils that, under the microscope, resemble threadlike fibers. What causes tau to misfold and lose function has long been a mystery.

A University of Pennsylvania, Philadelphia, study using kidney cells suggests a domino effect in which misfolded tau causes normal tau to misfold (Guo and Lee, 2011). The researchers found that minute quantities of misfolded tau introduced into cultured cells expressing normal tau caused the tau to form fibrils like those seen in the Alzheimer's brain. In addition, the researchers found that the cells soaked up the misfolded tau from the fluid surrounding them. Assuming that brain cells also take up tau, this study suggests a route by which tau pathology could spread from one neuron to another, as it appears to do in Alzheimer's disease.

As Alzheimer's disease progresses, tau pathology spreads from one brain region to another in a consistent pattern Tangles appear first in the entorhinal cortex, next in the hippocampus, and then in the cerebral cortex. These brain regions are connected to one another via synapses that create communication networks.

Research groups at Columbia University, New York City, and Harvard University, Cambridge, MA, have now shown that abnormal tau spreads from one brain region to the next by moving across synapses (Liu et al., 2012; de Calignon et al., 2012). Each research group performed similar experiments in which they created experimental mice that expressed mutant human tau only in the entorhinal cortex. As the mice aged, the mutant tau gradually spread across the connected brain regions. As the abnormal human tau appeared in each brain region, it clumped together with normal mouse tau to form tangles and damage synapses.

These studies demonstrate one mechanism by which Alzheimer's pathology can spread from one brain region to another. They also suggest a possible target for therapies that might delay or prevent disease onset and progression.