On 10 December, Dr. Hendrik Wesseling, Prof. Judith Steen and colleagues published an article in Cell, showing that tau accumulates successive mutations that promote protein aggregation in Alzheimer’s disease.
The accumulation of tangled aggregates of tau protein in the brain is one of the pathological hallmarks of Alzheimer’s disease (AD), with recent studies indicating that disease-associated tau can spread through the brain via neuronal connections. Thanks to technological advances in microscopy and proteomics, researchers have found that aggregated tau has many post-translational modifications (PTMs), which may account for its tendency to tangle. PTMs are subtle chemical changes that determine how complex proteins are folded, by altering their electrical charge, structure and interactions with each other.
In their Cell article, Dr. Wesseling and colleagues set out to determine the importance of different tau PTMs in AD, to understand how these accumulating modifications might cause tau aggregation and how this varies between individuals with AD. Extracting tau proteins from postmortem brain samples donated by 49 people with AD and 42 unaffected peers, they performed proteomics analyses to generate a high-resolution map of the different tau PTMs detected in these samples. People with AD had over 100 times the amount of insoluble, pathological tau compared to their unaffected peers, enriched with a particular isoform of tau protein. Looking more closely at the insoluble tau fraction, the researchers observed larger amounts of certain tau PTMs from the brains of people with advanced, symptomatic AD, with some heterogeneity between disease groups. They also observed successive accumulation of different tau PTMs at different stages of AD, suggesting that tau collects different, tangle-causing modifications as the disease progresses.
https://www.sciencedirect.com/science/article/pii/S0092867420313933
