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 Aß-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-TTK21induced 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 Overall design: TTK21, an activator of the acetyltransferase function of CBP/p300 when conjugated with glucose-based carbon nanospheres (CSP), hence termed as CSP-TTK21 (Chatterjee et al., 2013), restored acetylation of histone H2B in the hippocampus of THY-Tau22 mice, a mouse model with AD-related Tau pathology (Chatterjee et al., 2018). Moreover, CSP-TTK21 also upregulated the expression of plasticity-related genes and improved spatial memory in these mice. In this study, we found that CSP-TTK21 could also rescue synaptic plasticity deficits caused by acute Aß exposure in the CA1 area of rat hippocampal slices. We showed that CSP-TTK21 could restore long-term potentiation and late-associative plasticity induced by high-frequency tetanization and theta burst stimulation. Furthermore, we demonstrated that this rescue of functional synaptic plasticity was concomitant with the CSP-TTK21-mediated restoration of plasticity-related gene expression.