The last five years have seen great efforts to develop therapeutics to treat Alzheimer’s disease, but sadly, they have failed in the clinic to treat humans suffering from this horrible disease.
In a recent study at the University of Pennsylvania, researchers found that Alzheimer’s Disease is driven by epigenetic changes—how and when certain genes are turned on and off—in the brain.
They used post-mortem brain tissue to compare healthy younger and older brain cells to those with Alzheimer’s Disease.
They found evidence that epigenetic regulators disable protective pathways and enable pro-disease pathways in those with the disease.
The study is published in Nature Genetics. One author is Raffaella Nativio, Ph.D.
In the study, the researchers tried a completely different approach to reveal the critical changes in brain cells, and their findings show epigenetic changes are driving the disease.
Epigenetic changes alter gene expression without DNA mutation, but rather by marking proteins that package and protect DNA, called histones.
The activity of epigenetic regulators can be inhibited by drugs, and hence the researchers are excited that this may be an Achilles’ heel of Alzheimer’s that can be attacked by new therapeutics.
The team integrated many large-scale cutting-edge approaches of RNA, protein, and epigenomic analyses of postmortem human brains to interrogate the molecular pathways involved in Alzheimer’s.
They found the upregulation of transcription- and chromatin-related genes, including central histone acetyltransferases for marks that open up the chromatin.
They also found these marks as enriched in Alzheimer’s. The findings were tested functionally in a fly model, to show that increasing these marks exacerbated Alzheimer’s Disease-associated effects.
The results showed that there is a reconfiguration of the epigenomic landscape—that’s the DNA genome plus associated proteins—normally with age in the brain.
These changes fail to occur in Alzheimer’s and instead, other changes occur.
These findings suggest that Alzheimer’s Disease involves a reconfiguration of the epigenomic landscape.
The identification of this process highlights potential strategies to modulate these marks for early-stage disease treatment.
The team says the next step is to identify mechanisms underlying the protective and degradative pathways, which will lead to a more targeted approach for Alzheimer’s Disease therapy.
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