HDAC3 inhibition increases the expression levels of the Amyloid Precursor Protein
Magdalena Sastre, Ilaria Palmisano, Ben Taylor, Nicola Davis- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Epigenetic‐based interventions have recently garnered attention as potential therapies for Alzheimer’s disease (AD). Histone deacetylases (HDACs) represent an interesting target for neurodegenerative diseases therapies, since HDAC inhibitors have been shown to have the ability to reinstate memory even after neuronal loss. Particularly, HDAC3 inhibition has been shown to enhance long‐term memory and reduce amyloid‐β in AD models, although the molecular mechanisms behind these effects are unclear. The aim of this study was to characterise the effects of HDAC3 inhibition on the mechanisms of generation and degradation of Aβ using in vitro and in ex vivo models of AD
Method
N2a mouse neuroblastoma cells overexpressing the Swedish mutation (N2asw) as well as organotypic brain cultures (OBCs) of 5XFAD mice were incubated with various concentrations of the HDAC3 selective inhibitor RGFP966 (0.1‐10 μM) for 24h.
Result
Treatment with HDAC3 inhibitor RGFP966, led to a 4% increase on Aβ42 levels in N2a cells, associated with elevated levels carboxy‐terminus fragments (CTFs) and APP protein expressions as well as APP mRNA levels. In vitro chromatin immunoprecipitation (ChIP) analysis in N2a cells, revealed enriched HDAC3 binding at APP promoter regions. The increase in APP expression was also detected in OBCs from 5XFAD mice incubated with 1 μM RGFP966, without significant changes in Aβ secretion. In addition, mRNA sequencing in OBCs revealed that HDAC3 inhibition affects neuronal regenerative pathways, in particular linked to neurogenesis, neuronal differentiation, axonogenesis, resulting in an increase in dendritic spine density.
Conclusion
These results suggest that the HDAC3 therapeutic role in AD involves the regulation of APP expression and regenerative pathways, leading to increased synaptic connectivity.