# Mechanisms underlying Tip60 HAT action in neuroprotection of cognitive function

> **NIH NIH R01** · DREXEL UNIVERSITY · 2020 · $388,425

## Abstract

ABSTRACT
 Impairment of epigenetic gene control mechanisms in the brain involving reduced histone acetylation
levels causes significant cognitive deficits that are a debilitating hallmark of most neurodegenerative
disorders, including Alzheimer's disease (AD). Accordingly, of the neural epigenetic modifications identified
to date, histone acetylation has been unequivocally linked to facilitating learning and memory by regulating
cognition gene expression programs via chromatin packaging control in neurons. Nevertheless, despite
the central importance of histone acetylation in higher order brain function, the specific histone
acetyltransferases (HATs) that generate these neuroepigenetic marks and their mechanisms of action in
neural epigenetic gene control in the brain remain largely unknown. We generated a robust Tip60;APP
Drosophila model system that enables us to modulate Tip60 HAT levels in neural circuits of choice under AD
associated amyloid precursor protein (APP) neurodegenerative conditions, in vivo. Its use led to our exciting
discovery that Tip60 is critical for cognitive processes based on its role in neural epigenetic gene control and
remarkably, promotes neuroprotection for multiple cognitive neural circuits impaired in the brain during early
AD associated neurodegenerative progression. Further, our new preliminary studies indicate that Tip60 HAT
function in cognitive gene control is impaired in the human AD hippocampus. Our findings have laid a solid
groundwork for this proposal and our goal for this project is to identify the mechanisms underlying Tip60 HAT
action in neuroprotective gene control using fly and mouse AD models, and to determine how these Tip60
epigenetic processes go awry in the brains of human AD patients. We hypothesize that Tip60 promotes
neuroprotection during the AD pathological process by epigenetically reprogramming gene sets in the brain
that together protect against synaptic impairment and apoptotic cell death, and thus promote cognitive
function. Using a combination of molecular, cellular, biochemical and chromatin based techniques, along with
behavioral assays, in Aim 1A we will use our Tip60;APP and Tip60;Aβ42 fly models to identify the full array of
Tip60 epigenetic reprogrammed genes, and verify their mammalian Tip60 epigenetic conservation in the
mouse brain. In Aim 1B we will test whether these Tip60 neuroprotective genes are epigenetically
misregulated in the human AD brain, as we predict. In Aim 2A, we will dissect the transcriptional
mechanisms for how Tip60 epigenetically reprograms neuroprotective genes using fly and mouse AD
models. In Aim 2B we will test whether these same Tip60 transcriptional regulatory complexes are disrupted
in the human AD brain, as we predict. Our studies will provide broad insights into novel Tip60 epigenetic
mechanisms underlying human neurodegenerative disorders such as Alzheimer's disease, and new
understanding into HAT based drug design for early therapeutic interven...

## Key facts

- **NIH application ID:** 9925845
- **Project number:** 5R01NS095799-04
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** FELICE ELEFANT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,425
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925845

## Citation

> US National Institutes of Health, RePORTER application 9925845, Mechanisms underlying Tip60 HAT action in neuroprotection of cognitive function (5R01NS095799-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9925845. Licensed CC0.

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