Alzheimer's disease (AD) 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 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 Aβ 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-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-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 Aβ₄₂ fly brain protects against AD functional pathologies that include Aβ plaque accumulation, neural cell death, cognitive deficits, and shorter life-span. Strikingly, Tip60 protects against Aβ₄₂-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.

阿尔茨海默病 (AD) 是一种与年龄相关的神经退行性疾病，其特征是淀粉样蛋白 β (Aβ) 斑块积聚、神经元细胞死亡和在疾病进展过程中恶化的认知缺陷。由组蛋白乙酰转移酶 (HAT) Tip60 减少和组蛋白去乙酰化酶 2 (HDAC2) 水平增加之间的不平衡引起的组蛋白乙酰化失调可直接导致 AD 病理。然而，这种与 AD 相关的神经表观遗传学改变是否会响应 Aβ 肽的产生而发生，并且是否可以通过在神经退行性进展过程中增加 Tip60 水平来防止这种改变仍然未知。在这里，我们分析了仅由人类淀粉样蛋白-β 产生的果蝇大脑中早期和晚期 AD 病理学中的 Tip60 HAT/HDAC2 动力学和转录组范围内的变化₄₂ . 我们表明，在 Aβ 斑块积聚持续到 AD 晚期阶段之前的早期神经退行性阶段，早期 Aβ ₄₂诱导导致 Tip60 HAT/HDAC2 平衡的破坏。相关的全转录组研究揭示了我们将生物过程分类为短暂（仅限早期）、迟发（仅限后期）和恒定（两者）的生物过程的改变。增加 Aβ ₄₂果蝇大脑中的 Tip60 HAT 水平可防止 AD 功能性病变，包括 Aβ 斑块积聚、神经细胞死亡、认知缺陷和更短的寿命。引人注目的是，Tip60 可防止 Aβ ₄₂- 在神经变性的早期和晚期通过不同的机制诱导转录组改变。我们的研究结果揭示了 AD 早期和晚期阶段神经表观遗传基因变化的不同模式和 Tip60 神经保护作用，可以作为 AD 的早期生物标志物，并支持 Tip60 在 AD 进展过程中的治疗潜力。