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Alzheimer's Disease Linked to Epigenetic Changes in Multi-Omic Study

NEW YORK – Brain samples from Alzheimer's disease patients who died show a shift in transcriptional regulation and chromatin structure, according to new research from a team led by researchers at the University of Pennsylvania.

"Our findings provide mechanistic insights on [Alzheimer's disease] progression and highlight alternative avenues for potential intervention," co-corresponding authors Shelley Berger and Nancy Bonini, both researchers at UPenn, and their colleagues wrote in a study appearing in Nature Genetics on Monday.

Using a combination of RNA sequencing, liquid chromatography and mass spectrometry, 5-hydroxymethylcytosine profiling, and chromatin immunoprecipitation sequencing (ChIP-seq) focused on several histone modifications, the researchers characterized transcriptomic, proteomic, and epigenomic features in post-mortem brain samples from dozens of individuals with or without Alzheimer's disease.

In particular, the team's findings highlighted H3K27ac and H3K9ac histone modification gains in brain samples from Alzheimer's disease patients, along with shifts in related enzyme activity, suggesting that these histone modifications may have a previously unappreciated role in the condition.

The multi-omic experiments "identify histone modifications associated with [Alzheimer's disease] and reveal that H3K27ac and H3K9ac gains in [Alzheimer's disease] impact disease pathways by dysregulating transcription- and chromatin-gene feedback loops," the authors reported.

While it is well known that brain cells from individuals with late-onset Alzheimer's disease tend to show beta-amyloid buildup and features known as neurofibrillary tangles, the team explained, less is known about the molecular pathways and processes that go awry in those with the neurodegenerative disease, particularly when it comes to epigenetic features beyond cytosine DNA methylation profiles.

In an effort to get a clearer look at potential epigenetic contributors to Alzheimer's disease, the researchers assessed frozen post-mortem brain samples from 12 individuals with Alzheimer's disease, 10 unaffected individuals with the same average age, and eight unaffected individuals from a slightly younger age group, focusing on a lateral temporal lobe region that is known to be affected during early-stage Alzheimer's disease.

"Given the complexity of the aging and neurodegenerative processes, and their interrelation, we performed a comprehensive multi-omics analysis of brains affected with [Alzheimer's disease] versus the brains of old and younger controls," they wrote, noting that a "dataset of brains from healthy younger individuals was included to discriminate changes related to aging from those specific to [Alzheimer's disease]."

When the team compared available RNA-seq data from age group-matched individuals with or without Alzheimer's disease, it saw an Alzheimer's disease-related decrease in the expression of more than 400 genes, though 421 genes had enhanced expression in the diseased brain samples, including histone acetyltransferase enzyme-coding genes such as CBP, p300, or TRRAP — findings bolstered by proteomic data pointing to a rise in H3K27ac and H3K9ac histone modifications in the Alzheimer's-affected individuals.

With ChIP-seq experiments targeting histone post-translational modifications that came to the forefront from the transcriptomic and proteomic data, the researchers began teasing out the consequences of these histone modification shifts, which appeared to alter pathways related to chromatin structure, transcriptional regulation, and other disease-related pathways.

They went on to explore those findings further in a Drosophila fruit fly model of Alzheimer's disease, using altered versions of the histone post-translational modifications, and uncovered enhanced amyloid-beta toxicity in flies with enhanced H3K27ac and H3K9ac activity.

"Together, these findings suggest that [Alzheimer's disease] involves a reconfiguration of the epigenome, wherein H3K27ac and H3K9ac affect disease pathways by dysregulating transcription- and chromatin-gene feedback loops," the authors reported. "The identification of this process highlights potential epigenetic strategies for early-stage disease treatment."

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