CBP/P300 acetyltransferase activator CSPTTK21 restores memory

CBP/P300 acetyltransferase activator CSPTTK21 restores memory and plasticity dysfunctions in a
tau mouse model.
Raphaelle CASSEL 1 (*), Anne SCHNEIDER-ANTHONY 1 (*), Snehajyoti CHATTERJEE 1, Olivier BOUSIGES 1,
2
, Manoj KUMAR 3, Sarmistha HALDER SINHA 3, Piyush Kumar CHATURBEDY 4, Stéphanie LE GRAS 5,
Celine KEIME 5, Karine MERIENNE 1, Frédéric BLANC 2, Luc BUEE 6, David BLUM 6, Muthusamy
ESWARAMOORTHY 4, Jean-Christophe CASSEL1, Tapas KUNDU 3, Anne-Laurence BOUTILLIER 1
(1) Laboratory of Cognitive and Adaptive Neuroscience, UMR 7364 CNRS/University of
Strasbourg, 12 rue Goethe, 67000 Strasbourg, FRANCE
(2) Hopitaux Universitaires de Strasbourg, 1 rue Molière, 67000 Strasbourg, FRANCE
(3) Transcription and Disease Laboratory, Jawaharlal Nehru Centre for Advanced Scientific
Research, Jakkur P.O, Bangalore-560064, INDIA.
(4) Chemistry and Physics of Materials Unit, Jawaharlal Nehru Centre for Advanced Scientific
Research, Jakkur P.O, Bangalore-560064, INDIA.
(5) Institut de Genetique et Biologie Moleculaire et Cellulaire, CNRS/INSERM/University of
Strasbourg -UMR7104, Illkirch, FRANCE
(6) Université Lille-Nord de France, UDSL, Inserm U837, Jean-Pierre Aubert Research Centre,
IMPRT, CHRU, 59000 Lille, FRANCE
(* )
equal contribution to the work
Alzheimer’s disease (AD) is a common neurodegenerative disorder characterized by progressive
memory loss. The underlying causes are poorly understood and effective treatments are still under
intense investigations. Several studies point to new therapeutic interventions by modulating brain
acetylation levels with the use of histone deacetylase (HDAC) inhibitors. We recently described a new
molecule (CSP-TTK21) that promotes CBP acetyltransferase activation in the brain after
intraperitoneal injection. In the current study, we used a transgenic mouse model of tauopathy (tg22
strain) that develops neurofibrillary tangles (NFTs) and memory impairments, to assess the potential
therapeutic effect of CSPTTK21. We found that the levels of the acetyltransferase CBP were impaired
in the hippocampus of the tg22 model, especially in Tau-positive neurons. In addition, a global
decrease of H2Bac acetylation (H2Bac), a CBP-targeted histone mark, was observed at a time where
tg22 mice presented spatial memory impairments. ChIP-sequencing experiments confirmed that this
mark was altered, showing significant decreases of H2Bac at gene loci important for learning and
memory. Remarkably, CSP-TTK21 treatment fully rescued long term retention of spatial memory
performances and specifically increased H2Bac levels at learning and memory gene loci in the
hippocampus of tg22 mice. How this translates on gene expression is currently being evaluated.
Finally, we found that CBP levels were severely decreased in post-mortem brains from AD patients.
Our results strongly support the view that improving CBP histone acetyltransferase activity with
molecules such as CSP-TTK21 stands as a valuable epigenetic therapeutic option for the treatment of
memory and plasticity dysfunctions associated with neurodegenerative conditions.

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