Background: Previous research has shown that epigenetic dysregulation occurs in Alzheimer’s disease (AD). In AD, excitatory neurons are more vulnerable for dysfunction, degeneration, and death than inhibitory neurons. However, cell type-specific epigenetic signatures have been challenging to produce and most epigenetic studies in AD have used whole brain homogenate. Here, we investigate the DNA methylation and nucleosome occupancy of the vulnerable excitatory neurons across the early and late stages of human sporadic AD.
Methods: Excitatory neuronal nuclei were purified by fluorescence activated nuclei sorting (FANS) from unfixed human brain tissue from the inferior temporal gyrus (ITG; n=10 for each low, intermediate, and high AD pathology cases). Then, nucleosome occupancy and methylome-sequencing (NOMe-seq) was performed to investigate the DNA methylation and nucleosome landscapes of this neuronal subpopulation. To determine the AD pathology load in the ITG, amyloid plaque and tau loads were quantitated in fixed tissue sections from the same cohort.
Results: Genome-wide maps of DNA methylation and nucleosome occupancy were generated from excitatory neurons across the different stages of human sporadic AD. The DNA methylation and nucleosome occupancy landscape in excitatory neurons was significantly different in low pathology cases (controls) compared to intermediate/high pathology AD cases (p<0.05). A subset of genomic loci also exhibited DNA methylation that altered in tandem with pathology load (p<0.05).
Conclusion: These results are the first to demonstrate that sporadic AD progression is associated with alterations in DNA methylation and nucleosome positioning within vulnerable excitatory neurons. The identification of these epigenetic signatures will provide a valuable resource for future research aimed at developing neuroprotective therapeutic for sporadic AD.