Taking a break can be a great thing for our aging brains, it gives us a chance to unwind and open ourselves up to new ideas. However, it’s possible to have too much of a good thing, where overly relaxed chromatin can wreak havoc on an aging neuron and drive pathological changes!
One of the hallmarks for diagnosing Alzheimer ’s disease is the presence of tangled tau proteins in neurons. Although normal aging and Alzheimer ’s disease are associated with changes in histone acetylation, research in Drosophila suggests that aggregating tau might relax regions of the genome that are usually tightly repressed. By utilizing ChIP-seq to investigate the active histone mark H3K9ac, the labs of David Bennett (Rush University, Chicago) and Phillip DeJager (Columbia University, New York) investigated this phenomenon in over 600 aged human brain samples and found that:
- H3K9ac associates with the amount of tau protein in the dorsolateral prefrontal cortex, regardless of whether the subject had been diagnosed with Alzheimer’s disease
- By integrating their peaks with previously published data, including some from the same brain samples, the team found that tau-related H3K9ac peaks overlap with areas of decreased DNA methylation and increased gene expression in neurons
- Adult tau mutant mice, which are used to model Alzheimer’s disease, have similar H3K9ac profiles in their hippocampus, before any cells are lost to neurodegeneration
Next, the team turned to cultured forebrain neurons, which were differentiated from a line induced pluripotent stem cells with a familial Alzheimer’s disease mutation, where:
- ATAC-seq revealed that tau-related open chromatin peaks overlap with H3K9ac peaks from the post mortem cortex
- Tau-associated regions in cells are more likely to be located in areas of heterochromatin near the nuclear lamina, while in the human cortex, tau has more of an impact on genomic segments further away from the nuclear membrane
- The small molecule 17-DMAG, which inhibits heat shock protein 90, can protect cells from the chromatin rearranging impact of mutant tau when added to cell cultures for 24 hours
As tau accumulates in aging neurons, especially in Alzheimer’s Disease, it might take its job as a chromatin relaxer too far. Luckily, it looks like the 17-MAG can add a little work-life balance to the equation and keep tau in check.
If your job has you all wound up, give your brain a break and relax with Nature Neuroscience, January 2019.