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bioRxiv · 10.1101/2020.06.09.142885

Transcriptome analysis uncovers distinct modes of epigenetic gene changes in early versus late stages of amyloid-β induced Alzheimer's disease pathology

Zhang, H.·Karisetty, B. C.·Bhatnagar, A.·Armour, E. M.·Beaver, M.·Roach, T. V.·Mortazavi, S.·Mandloi, S.·Elefant, F.
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Abstract

Alzheimers disease (AD) is an age-related neurodegenerative disorder hallmarked by amyloid-{beta} (A{beta}) plaque accumulation, neuronal cell death, and cognitive deficits that worsen during disease progression. Histone acetylation dysregulation, caused by an imbalance between reduced histone acetyltransferases (HAT) Tip60 and increased histone deacetylase 2 (HDAC2) levels, can directly contribute to AD pathology. However, whether such AD-associated neuroepigenetic alterations occur in response to A{beta} peptide production and can be protected against by increasing Tip60 levels over the course of neurodegenerative progression remains unknown. Here we profile Tip60 HAT/HDAC2 dynamics and transcriptome-wide changes across early and late stage AD pathology in the Drosophila brain produced solely by human amyloid-{beta}42. We show that early A{beta}42 induction leads to disruption of Tip60 HAT/HDAC2 balance during early neurodegenerative stages preceding A{beta} plaque accumulation that persists into late AD stages. Correlative transcriptome-wide studies reveal alterations in biological processes we classified as transient (early-stage only), late-onset (late-stage only), and constant (both). Increasing Tip60 HAT levels in the A{beta}42 fly brain protects against AD functional pathologies that include A{beta} plaque accumulation, neural cell death, cognitive deficits, and shorter life-span. Strikingly, Tip60 protects against A{beta}42-induced transcriptomic alterations via distinct mechanisms during early and late stages of neurodegeneration. Our findings reveal distinct modes of neuroepigenetic gene changes and Tip60 neuroprotection in early versus late stages in AD that can serve as early biomarkers for AD, and support the therapeutic potential of Tip60 over the course of AD progression.

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Zhang, H., Karisetty, B. C., Bhatnagar, A., Armour, E. M., Beaver, M., Roach, T. V., Mortazavi, S., Mandloi, S., Elefant, F.. 2020-06-11. Transcriptome analysis uncovers distinct modes of epigenetic gene changes in early versus late stages of amyloid-β induced Alzheimer's disease pathology. https://doi.org/10.1101/2020.06.09.142885

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