Summary: A new study reports researchers have successfully reversed memory loss in fly models of Alzheimer’s disease by restoring the balance between to enzymes that regulate gene expression.
Source: Drexel University.
Researchers from Drexel University reversed symptoms of Alzheimer’s disease in fruit flies by restoring the balance between two epigenetic enzymes that regulate gene expression, a study shows.
Early in the progression of Alzheimer’s disease, cognitive impairment (such as difficulties with learning and memory) may be tied to the presence of elevated levels of the HDAC2 enzyme. HDAC2 helps control how genes linked to learning and memory are expressed. It appears that when HDAC2 overwhelms the enzyme it is paired with, which is called Tip60 HAT, it represses genes and leads to problems with neuroplasticity – the brain’s ability to adapt to new stimuli or recall reactions to stimuli it already encountered.
But a research team led by Priyalakshmi Panikker, a PhD student, and Felice Elefant, PhD, an associate professor, both in Drexel’s College of Arts and Sciences, performed tests in flies and found that if they added extra Tip60 HAT in the brain of flies that displayed symptoms close to Alzheimer’s disease, the balance between the enzymes could be successfully restored. When that balance came back, behaviors the team had taught the flies were able to be learned again and remembered.
“Our findings strongly support the concept of exploring the efficacy of specific Tip60 HAT activators, as well as identifying and manipulating additionally misregulated Tip60 target genes,” Elefant said.
Elefant, Panikker and their team – whose findings were published in the Journal of Neuroscience – looked at how Alzheimer’s disease affected flies early in their development, during their larval stages, to catch what might happen in Alzheimer’s well before the tell-tale symptoms arise.
“Many researchers that study Alzheimer’s disease utilize human post-mortem samples, and thus, they are not looking at what is happening during the early progression of neurodegeneration, including whether we can correct what is happening during these early stages ,” Elefant said.
For the study, flies were taught to associate a certain odor with sucrose – table sugar, which flies eat and is a positive reinforcement. After being exposed to the scent paired with sugar, the flies learned to move towards the scent even without the sugar present.
Flies that modeled Alzheimer’s disease showed no difference in their reaction to the smell they had earlier been condition to. This showed that their ability to learn and remember this association was negatively affected.
But once Tip60 HAT was introduced in the brain to correct the identified Tip60 HAT/HDAC2 imbalance, these flies showed a reaction time comparable to the ones without the Alzheimer’s type of condition. This indicated that they recovered their ability to learn and remember after the epigenetic balance was reintroduced.
Moreover, when researchers identified a collection of genes related to brain function that had been repressed in the flies – due to elevated HDAC2 – an introduction of increased Tip60 HAT levels in the brain restored regular function in 9 of the 11 genes tested.
The results Panikker and Elefant found were encouraging. More testing is needed, but Elefant’s goal is to find new avenues for gene therapy.
“When people age, they have a loss of memory but it’s not because there are mutations in their genes,” Elefant said. “It’s the way they’re packaged. They’re distorted. And we’re seeing non-invasive ways we might be able to prevent that early on.”
Source: Frank Otto – Drexel University
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is adapted from the Drexel University news release.
Original Research: Abstract for “Restoring Tip60 HAT/HDAC2 Balance in the Neurodegenerative Brain Relieves Epigenetic Transcriptional Repression and Reinstates Cognition” by Priyalakshmi Panikker, Song-Jun Xu, Haolin Zhang, Jessica Sarthi, Mariah Beaver, Avni Sheth, Sunya Akhter and Felice Elefant in Journal of Neuroscience. Published May 9 2018.
Restoring Tip60 HAT/HDAC2 Balance in the Neurodegenerative Brain Relieves Epigenetic Transcriptional Repression and Reinstates Cognition
Cognitive decline is a debilitating hallmark during preclinical stages of Alzheimer’s disease (AD), yet the causes remain unclear. Because histone acetylation homeostasis is critical for mediating epigenetic gene control throughout neuronal development, we postulated that its misregulation contributes to cognitive impairment preceding AD pathology. Here, we show that disruption of Tip60 histone acetlytransferase (HAT)/histone deacetylase 2 (HDAC2) homeostasis occurs early in the brain of an AD-associated amyloid precursor protein (APP) Drosophila model and triggers epigenetic repression of neuroplasticity genes well before Aβ plaques form in male and female larvae. Repressed genes display enhanced HDAC2 binding and reduced Tip60 and histone acetylation enrichment. Increasing Tip60 in the AD-associated APP brain restores Tip60 HAT/HDAC2 balance by decreasing HDAC2 levels, reverses neuroepigenetic alterations to activate synaptic plasticity genes, and reinstates brain morphology and cognition. Such Drosophila neuroplasticity gene epigenetic signatures are conserved in male and female mouse hippocampus and their expression and Tip60 function is compromised in hippocampus from AD patients. We suggest that Tip60 HAT/HDAC2-mediated epigenetic gene disruption is a critical initial step in AD that is reversed by restoring Tip60 in the brain.
SIGNIFICANCE STATEMENT Mild cognitive impairment is a debilitating hallmark during preclinical stages of Alzheimer’s disease (AD), yet its causes remain unclear. Although recent findings support elevated histone deacetylase 2 (HDAC2) as a cause for epigenetic repression of synaptic genes that contribute to cognitive deficits, whether alterations in histone acetlytransferase (HAT) levels that counterbalance HDAC2 repressor action occur and the identity of these HATs remain unknown. We demonstrate that disruption of Tip60 HAT/HDAC2 homeostasis occurs early in the AD Drosophila brain and triggers epigenetic repression of neuroplasticity genes before Aβ plaques form. Increasing Tip60 in the AD brain restores Tip60 HAT/HDAC2 balance, reverses neuroepigenetic alterations to activate synaptic genes, and reinstates brain morphology and cognition. Our data suggest that disruption of the Tip60 HAT/HDAC2 balance is a critical initial step in AD.