Given the unfortunate failure of many treatment strategies for late-stage Alzheimer’s disease, researchers recently sought to gain some fresh new perspective from multiple angles by mounting a three-pronged transcriptomic, proteomic, and epigenomic attack to decipher the mechanisms controlling disease progression. Excitingly, the team behind this study now highlight the possibility of an early-stage epigenetic therapy for this devastating condition.
This tri-mendous new study from the dynamic duo of Nancy M. Bonini and Shelley L. Berger (University of Pennsylvania, Philadelphia, PA, USA) comes hot on the heels of previous research from the group that described the loss of H4K16 acetylation, highlighted as an age-related protective epigenetic pathway, in the brains of Alzheimer’s patients. With their interest piqued by this disease-associated epigenetic alteration, the authors next fully explored this concept through multi-omics analyses in the hope of discovering any epigenomic reconfiguration that occurs before the intercellular beta-amyloid plaques and intracellular neurofibrillary tangles that correlate with neuronal death and loss of cognition during late-stage disease.
So let’s hear how Nativio and colleagues identified the pathways involved in early-stage Alzheimer’s through integrated transcriptomic, proteomic, and epigenomic analyses of the lateral temporal lobe, a region affected early in Alzheimer’s, of post-mortem human brains:
- RNA-seq-based transcriptomic analysis reveals the upregulation of transcription factor and chromatin modifier genes in Alzheimer’s samples
- Proteomic screening via nano liquid chromatography with tandem mass spectrometry highlights H3K27 and H3K9 acetylation as highly enriched post-translational modifications associated with Alzheimer’s, in agreement with the transcriptomic analysis
- ChIP–seq-based epigenomic profiling confirms the transcriptomic/proteomic findings and links a gain of H3K27 and H3K9 acetylation at genes related to transcription, chromatin, and disease pathways with Alzheimer’s
- Together, these findings suggest the existence of a self-reinforcing disease-associated feedback loop involved in disease progression
- The authors confirm a link between aberrant epigenetic activation and Alzheimer’s by showing the worsening of beta amyloid-driven neurodegeneration in a fly model of Alzheimer’s disease following an increase in H3K27 and H3K9 acetylation levels
Overall, these fascinating findings link Alzheimer’s and an epigenomic reconfiguration, thereby highlighting epigenetic interventions such as targeted histone deacetylation as potential treatment strategies during early-stage disease.
“Based on our findings, there is a reconfiguration of the epigenomic landscape normally with age in the brain,” states Nancy M. Bonini, one of the study leaders. “These changes fail to occur in Alzheimer’s and instead other changes occur. What’s remarkable is that the simple fruit fly Drosophila, in which we can express Alzheimer’s associated proteins and confer an Alzheimer’s effect, confirms that the specific types of changes to the epigenome we predict are associated with Alzheimer’s do exaggerate the toxicity of Alzheimer’s proteins.”
For more on how epigenetic modifications may represent the beginning and the end of Alzheimer’s disease, see Nature Genetics, September 2020.