Tip60 protects against amyloid-[beta]-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegeneration

Haolin Zhang

doi:10.17918/00000341

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by amyloid-[beta] (A[beta]) plaque accumulation, neurofibrillary tangles, neuronal apoptosis, and cognitive decline that worsens during disease progression. The development of AD is a complex interaction between genetic and environmental factors, in which epigenetic mechanisms play a crucial role. Histone acetylation dysregulation, caused by an imbalance between reduced histone acetyltransferase (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, are constant or dynamic, and can be protected against by increasing Tip60 levels throughout neurodegenerative progression remains unknown. In this study, we profile Tip60 HAT/HDAC2 dynamics and transcriptome-wide changes across early and late stages of AD pathology in the Drosophila melanogaster brain produced solely by human A[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). Specifically, transient gene expression changes feature gene expression regulation, contributing to the direct and precise cellular responses to early A[beta] toxicity. In contrast, late gene expression changes feature a non-specific cellular metabolic defect. Neuroinflammation and metabolic inhibition gene changes are consistently present throughout disease development. Increasing Tip60 HAT levels in the A[beta]42 fly brain protects against AD functional pathologies, including 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. In the early stage, restoring Tip60 HAT/HDAC2 balance can specifically protect against the same gene ontology processes that are altered by A[beta]42 at the transcriptional level, staving off AD progression. Although Tip60 restoration can recover many neural functions in the late stage, it loses specificity against A[beta]42-misregulated gene sets due to increasingly strengthened proteopathic stress to the cells. Our findings reveal different 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.

Tip60 protects against amyloid-[beta]-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegeneration

Files and links (1)

Abstract

Metrics

Details

Tip60 protects against amyloid-[beta]-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegeneration

Files and links (1)

Abstract

Metrics

Details

Drexel University Social media