T.Y. Patel1, A. Melukote1, M. Samples2,3, R. Kayed2,3, M. Montalbano2,3 1University Of Texas Medical Branch, John Sealy School Of Medicine, Galveston, TX, USA 2University Of Texas Medical Branch, Mitchell Center For Neurodegenerative Diseases, Galveston, TX, USA 3University Of Texas Medical Branch, Department Of Neurology, Neuroscience, And Cell Biology, Galveston, TX, USA
Introduction:
Alzheimer’s Disease (AD) is a neurodegenerative disorder hallmarked by the pathological accumulation of tau protein aggregates, which are implicated in cognitive decline and neuronal death. Emerging evidence underscores a critical interplay between tau pathology and histone modifications, particularly H3K4me3 (tri-methylation at lysine 4 of histone H3) and H3K9me3 (tri-methylation at lysine 9 of histone H3), which are integral to chromatin remodeling and gene expression regulation. The aberrant regulation of these histone marks is believed to contribute to the epigenetic landscape of AD, potentially driving the progression of neurodegeneration.
Methods:
Primary cortical neurons (PCNs) isolated from wild-type murine models were exposed to recombinant Tau oligomers (rTauO) at a concentration of 0.5 µM for 24 hours. Post-treatment, neurons were fixed in paraformaldehyde and subjected to immunofluorescence staining for the detection of H3K4me3 and H3K9me3. Confocal microscopy was employed to capture high-resolution images, which were subsequently analyzed using ImageJ and GraphPad software to quantify changes in histone modification levels and to assess chromatin structural alterations.
Results:
rTauO treatment induced a significant reduction in H3K4me3 levels, as evidenced by a pronounced decrease in mean fluorescence intensity, indicating a potential downregulation of gene transcription associated with neuronal function. Conversely, a significant increase in H3K9me3 levels was observed, characterized by an elevated mean integrated density, suggesting enhanced heterochromatin formation and transcriptional repression. Notably, three-dimensional analysis revealed that H3K9me3-enriched regions occupied more than 50% of the nucleolar volume in rTauO-treated neurons, further highlighting the extensive chromatin remodeling induced by tau pathology.
Conclusion:
This study provides compelling evidence that tau pathology in Alzheimer’s Disease is closely associated with epigenetic modifications, specifically the depletion of H3K4me3 and the accumulation of H3K9me3. These alterations likely contribute to the neurodegenerative process by facilitating the repression of neuronal genes and promoting heterochromatin formation, thereby exacerbating the disease’s pathological features. Elucidating the role of histone modifications in AD pathogenesis offers promising insights for the development of targeted epigenetic therapies aimed at mitigating tau-induced neurotoxicity and disease progression.