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

  • Aging Cell. 2022 Sep;21(9):e13675. doi: 10.1111/acel.13675.
Akash K Singh  1 ,  Sin H Neo  2 ,  Christine Liwang  2 ,  Karen K L Pang  2 ,  Jason C K Leng  2 ,  Sarmistha H Sinha  1 ,  Mahesh S Shetty  2  3 ,  Madavan Vasudevan  4 ,  Vinay J Rao  1 ,  Ila Joshi  1 ,  Muthusamy Eswaramoorthy  5 ,  Maria V Pavon  2 ,  Ang R Sheila  2 ,  Sheeja Navakkode  2  6 ,  Tapas K Kundu  1  7 ,  Sreedharan Sajikumar  2  8  9
Affiliations
  • 1. Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India.
  • 2. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 3. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
  • 4. Department of Neuroscience and Pharmacology, Iowa Neuroscience Institute, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
  • 5. Theomics International Pvt Ltd, Bangalore, India.
  • 6. Chemistry and Physics of Materials Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India.
  • 7. Division of Neuroscience and Aging Biology, CSIR-Central Drug Research Institute Sector 10, Lucknow, Uttar Pradesh, India.
  • 8. Life Science Institute Neurobiology Programme (LSI), National University of Singapore, Singapore, Singapore.
  • 9. Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
PMID: 35962576 DOI: 10.1111/acel.13675
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.

Keywords
CREB-binding protein; TTK21; long-term potentiation; synaptic tagging; synaptic tagging/ capture.
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