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

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.