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Journal article
Tip60 protects against amyloid-beta-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegeneration
Molecular and cellular neurosciences, v 109, 103570
01 Dec 2020
PMID: 33160016
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Alzheimer's 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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- Title
- Tip60 protects against amyloid-beta-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegeneration
- Creators
- Haolin Zhang - Drexel UniversityBhanu Chandra Karisetty - Drexel UniversityAkanksha Bhatnagar - Drexel UniversityEllen M. Armour - Drexel UniversityMariah Beaver - Drexel UniversityTiffany V. Roach - Drexel UniversitySina Mortazavi - Drexel UniversityShreya Mandloi - Drexel UniversityFelice Elefant - Drexel University
- Publication Details
- Molecular and cellular neurosciences, v 109, 103570
- Publisher
- Elsevier
- Number of pages
- 13
- Grant note
- 5R01NS095799-04 / National Institutes of Health (NIH) R01 grant; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000600365400003
- Scopus ID
- 2-s2.0-85095750794
- Other Identifier
- 991019168317704721
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- Web of Science research areas
- Neurosciences