Researchers from Drexel University’s College of Arts and Sciences and College of Medicine have found a potential new therapeutic target for Alzheimer’s disease. Expanding on their previous research on Tip60 histone acetyltransferase (HAT), known as the Tip60 enzyme, which controls genes that promote learning and memory in the brain, the Drexel research team generated small molecular compounds that activate Tip60 and restore deficits in the brain found in Alzheimer’s disease patients, such as gene expression programs linked to learning, memory and neurodegeneration. The study was published in Nature Communications.
“Many studies on Alzheimer's disease are focused on genetic causes,” said Felice Elefant, PhD, a professor in the College of Arts and Sciences. “But research has shown that over 90% of the causes of Alzheimer's disease cases are actually sporadic in nature, with severity dependent upon a complex interplay of genetics, age and environmental factors orchestrated in large part by neuroepigenetic – dynamic and reversible – mechanisms of gene control.”
Elefant added that because neuroepigenetic gene regulation in the brain is influenced by our external experiences, lifestyle choices and even the foods we eat, her lab explores how such neuroepigenetic gene control mechanisms go awry as people age, culminating into age related neurodegenerative disorders that include Alzheimer’s disease.
Elefant explained that in multiple neurodegenerative disorders, such as Alzheimer's disease, Parkinson’s diseases and Amyotrophic Lateral Sclerosis (ALS), these neuroepigenetic gene control processes are not playing the role that they should be, leading to losses in memory and other cognitive functions.
Neuroepigenetic gene control is moderated by acetylation – or a reaction – of histone proteins in the brain that control chromatin (DNA and protein) packaging. DNA is wound around these histones to form a compact chromatin state that is resistant to genes being turned on. The histone proteins are marked for acetylation causing chromatin to loosen, enabling DNA to become accessible for gene activation. But, Elefant explained, in age-related neurodegenerative disorders, like Alzheimer’s disease, there's a reduction of certain histone acetyltransferase (HAT) enzymes that “write” these histone acetylation marks, resulting in reduced histone acetylation in the brain that causes cognition genes to be turned off. One such specific HAT enzyme is called Tip60, which adds specific acetylation marks that are responsible for turning on the genes that promote learning and memory. In Alzheimer’s disease patient’s postmortem brains, they have found that the Tip60- HAT enzyme is significantly reduced.
Elefant went on to explain that by genetically increasing Tip60 in Drosophila – fruit fly – brains that model human Alzheimer’s disease, they observed reactivation of inappropriately turned off cognition linked genes and prevention of multiple neural processes impaired in Alzheimer’s disease, including learning and memory, early lethality, plaque formation and neurodegeneration.
“Our goal with this study was to develop a novel compound that specifically interacts with human Tip60 to enhance its HAT activity,” said Elefant. “We speculate these compounds will be useful in activating the residual Tip60 that's left in a patient’s brain with Alzheimer’s disease to restore cognition-linked gene expression profiles that, in turn, alleviate cognitive deficits and slow neurodegeneration progression.”
Most Alzheimer’s disease neuroepigenetic therapy research has focused on inhibiting the enzymes that remove histone acetylation. Although inhibitors are easier to develop, explained Elefant, blocking enzymes can cause non-specific hyperacetylation that further impairs cognition. In contrast, generating selective Tip60 activators for Alzheimer’s disease enables site specific, cognition-linked acetylation marks to be maintained, allowing for a more specific neuroepigenetic based therapeutic that does not cause detrimental side-effects.
According to Elefant, small molecular compounds that specifically activate Tip60 have never been developed before. Elefant’s collaborators, Akanksha Bhatnagar, PhD, a postdoctoral researcher at the University of Pennsylvania, and Sandhya Kortagere, PhD, a professor in Drexel’s College of Medicine, created the compound by using a computational virtual screening of molecules – known as pharmacophore-based virtual screening – to find one that can bind and theoretically activate Tip60’s HAT domain, then had the compound manufactured and tested in a fruit fly that models human Alzheimer’s disease.
Drosophila fruit flies serve as effective models to test the compounds on neurological disorders. Human Alzheimer's disease can be effectively modeled in the fly that exhibit hallmarks of human Alzheimer’s disease pathology, including Abeta plaques in the brain, early lethality, repression of cognition genes and learning and memory deficits. Alzheimer’s disease fly models also enable researchers to study early neurodegenerative progression, which is impossible in postmortem human tissue. Elefant added that they do also use human disease tissues to make sure that all of their findings in the fly model are clinically relevant.
Tests of the compounds proved extremely effective at multiple levels. Several compounds showed high Tip60 binding affinity, enhanced Tip60 HAT action in vitro prevented neuronal deficits and early lethality in a Drosophila model of Alzheimer’s disease and remarkably, restored expression of repressed cognition genes in the Alzheimer’s disease brain, underscoring the compound’s ability to target specific areas and its therapeutic effectiveness.
“These therapeutic chemical compounds are very small, which
is important because in humans, and even in flies, it has to be able to pass
the blood
brain barrier,” said Elefant.
Elefant explained that this is just the first step –
generating an activator compound, characterizing the compound and showing that
it works, “is a big deal in the field because it's very difficult to develop a
compound that can specifically bind and restructure a protein to make it more
active.”
The next step is to optimize the compound, make sure it is
safe in humans, ensure that it can be optimized for metabolism and for crossing
the blood brain barrier, see if it can work in mammalian Alzheimer’s disease
models, and then ultimately, in clinical trials.
The research team noted the potential of these findings in
other neurodegenerative diseases. Elefant and her PhD student, Gu Gu Nge, and
several biology undergraduate researchers in her lab are exploring whether
these compounds have potential for rescuing defects in Parkinson’s,
Huntington’s and Amyotrophic Lateral Sclerosis (ALS) in fruit flies.
Read the full article here: https://www.nature.com/articles/s41467-025-58496-w.