Glucose derived carbon nanosphere (CSP) conjugated TTK21, an activator of the histone acetyltransferases CBP/p300, ameliorates amyloid‐beta 1–42 induced deficits in plasticity and associativity in hippocampal CA1 pyramidal neurons
Akash Kumar Singh, Sin Hui Neo, Christine Liwang, Karen Ka Lam Pang, Jason C. K. Leng, Sarmistha Halder Sinha, Mahesh Shivarama Shetty, Madavan Vasudevan, Vinay J. Rao, Ila Joshi, Muthusamy Eswaramoorthy, María Vázquez Pavón, Ang R. Sheila, Sheeja Navakkode, Tapas K. Kundu, Sreedharan Sajikumar
Abstract
The master epigenetic regulator lysine acetyltransferase (KAT) p300/CBP plays a pivotal role in neuroplasticity and cognitive functions. Recent evidence has shown that in several neurodegenerative diseases, including Alzheimer's disease (AD), the expression level and function of p300/CBP are severely compromised, leading to altered gene expression causing pathological conditions. Here, we show that p300/CBP activation by a small-molecule TTK21, conjugated to carbon nanosphere (CSP) ameliorates Aβ-impaired long-term potentiation (LTP) induced by high-frequency stimulation, theta burst stimulation, and synaptic tagging/capture (STC). This functional rescue was correlated with CSP-TTK21-induced changes in transcription and translation. Mechanistically, we observed that the expression of a large number of synaptic plasticity- and memory-related genes was rescued, presumably by the restoration of p300/CBP mediated acetylation. Collectively, these results suggest that small-molecule activators of p300/CBP could be a potential therapeutic molecule for neurodegenerative diseases like AD.