Journal article
Tip60 HAT activators as therapeutic modulators for Alzheimer's disease
Nature communications, v 16(1), 3347
09 Apr 2025
PMID: 40199891
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Reduced histone acetylation in the brain causes transcriptional dysregulation and cognitive impairment that are key initial steps in Alzheimer's disease (AD) etiology. Unfortunately, current treatment strategies primarily focus on histone deacetylase inhibition (HDACi) that causes detrimental side effects due to non-specific acetylation. Here, we test Tip60 histone acetyltransferase (HAT) activation as a therapeutic strategy for selectively restoring cognition-associated histone acetylation depleted in AD by developing compounds that enhance Tip60's neuroprotective HAT function. Several compounds show high Tip60-binding affinity predictions in silico, enhanced Tip60 HAT action in vitro, and restore Tip60 knockdown mediated functional deficits in Drosophila in vivo. Furthermore, compounds prevent neuronal deficits and lethality in an AD-associated amyloid precursor protein neurodegenerative Drosophila model and remarkably, restore expression of repressed neuroplasticity genes in the AD brain, underscoring compound specificity and therapeutic effectiveness. Our results highlight Tip60 HAT activators as a promising therapeutic neuroepigenetic modulator strategy for AD treatment.
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Details
- Title
- Tip60 HAT activators as therapeutic modulators for Alzheimer's disease
- Creators
- Akanksha Bhatnagar - Drexel UniversityChristina M Thomas - Drexel UniversityGu Gu Nge - Drexel UniversityAprem Zaya - Drexel UniversityRohan Dasari - Drexel UniversityNeha Chongtham - Drexel UniversityBijaya Manandhar - Department of Biology, Papadakis Integrated Sciences Building, Drexel University, Philadelphia, PA, USASandhya Kortagere - Drexel UniversityFelice Elefant - Drexel University
- Publication Details
- Nature communications, v 16(1), 3347
- Publisher
- Nature
- Number of pages
- 15
- Grant note
- RF1NS095799 / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; Biology
- Web of Science ID
- WOS:001462202000002
- Scopus ID
- 2-s2.0-105002976622
- Other Identifier
- 991022048206004721
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- Web of Science research areas
- Neurosciences