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.Ministry of Education (MOE)Ministry of Health (MOH)National University of Singapore (NUS), Temasek LaboratoriesPublished versionThis work was supported by Ministry of Health (MOH-000641-00), Ministry of Education Academic Research Fund. Tier 3 (MOE2017- T3-1-002), and NUSMED-FOS Joint Research Programme (NUHSRO/2018/075/NUSMed-FoS/01) grants to S.S. A part of this work is also supported by NUHS Seed Fund (NUHSRO/2020/145/RO5+6/Seed-Sep/05). T.K.K. was supported by Department of Biotechnology, Government of India project grant (BT/PR11756/NNT/28/764/2014) and JC Bose National Fellowship grant (JBR/2020/000029). A.K.S. acknowledges the financial support provided by the JNCASR Research Fellowship