Tip60 HAT activators as therapeutic modulators for Alzheimer’s disease

Akanksha Bhatnagar, Christina M. Thomas, Gu Gu Nge, Aprem Zaya, Rohan Dasari, Neha Chongtham, Bijaya Manandhar, Sandhya Kortagere () and Felice Elefant ()
Additional contact information
Akanksha Bhatnagar: Drexel University
Christina M. Thomas: Drexel University
Gu Gu Nge: Drexel University
Aprem Zaya: Drexel University
Rohan Dasari: Drexel University
Neha Chongtham: Drexel University
Bijaya Manandhar: Drexel University
Sandhya Kortagere: Drexel University College of Medicine
Felice Elefant: Drexel University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-58496-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58496-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-58496-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().