2. Academic Validation
  3. 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

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

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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