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

Alzheimer9s disease is an age-related neurodegenerative disorder hallmarked by amyloid-β (Aβ) plaque accumulation, neuronal cell death, and cognitive deficits that worsen during disease progression. Histone acetylation dysregulation, caused by an imbalance between the histone acetyltransferases (HAT) Tip60 and histone deacetylase 2 (HDAC2), can directly contribute to AD pathology. Nevertheless, early and late-stage regulatory epigenetic alterations remain to be characterized. Here we profile Tip60 HAT/HDAC2 dynamics and transcriptional changes across early and late stage AD pathology in the Drosophila brain produced solely by human amyloid-β42. We show that early Aβ42 induction leads to disruption of Tip60 HAT/HDAC2 balance during early neurodegenerative stages preceding Aβ plaque accumulation that persists into late AD stages. Correlative transcriptome 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 Aβ42 fly brain protects against AD functional pathologies that include Aβ plaque accumulation, neural cell death, cognitive deficits, and shorter life-span. Strikingly, Tip60 also protects against Aβ42 induced transcriptomic alterations via distinct mechanisms during early and late stages of neurodegeneration. Our findings provide new insights into distinct modes of epigenetic gene alterations and Tip60 neuroprotection during early versus late stages in AD progression.