Open AccessReinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator
Author(s) -
Chatterjee Snehajyoti,
Cassel Raphaelle,
SchneiderAnthony Anne,
Merienne Karine,
Cosquer Brigitte,
Tzeplaeff Laura,
Halder Sinha Sarmistha,
Kumar Manoj,
Chaturbedy Piyush,
Eswaramoorthy Muthusamy,
Le Gras Stéphanie,
Keime Céline,
Bousiges Olivier,
Dutar Patrick,
Petsophonsakul Petnoi,
Rampon Claire,
Cassel JeanChristophe,
Buée Luc,
Blum David,
Kundu Tapas K,
Boutillier AnneLaurence
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201708587
Subject(s) - chatterjee , philosophy , sociology , linguistics , bengali
Chromatin acetylation, a critical regulator of synaptic plasticity and memory processes, is thought to be altered in neurodegenerative diseases. Here, we demonstrate that spatial memory and plasticity ( LTD , dendritic spine formation) deficits can be restored in a mouse model of tauopathy following treatment with CSP ‐ TTK 21, a small‐molecule activator of CBP /p300 histone acetyltransferases ( HAT ). At the transcriptional level, CSP ‐ TTK 21 re‐established half of the hippocampal transcriptome in learning mice, likely through increased expression of neuronal activity genes and memory enhancers. At the epigenomic level, the hippocampus of tauopathic mice showed a significant decrease in H2B but not H3K27 acetylation levels, both marks co‐localizing at TSS and CBP enhancers. Importantly, CSP ‐ TTK 21 treatment increased H2B acetylation levels at decreased peaks, CBP enhancers, and TSS , including genes associated with plasticity and neuronal functions, overall providing a 95% rescue of the H2B acetylome in tauopathic mice. This study is the first to provide in vivo proof‐of‐concept evidence that CBP /p300 HAT activation efficiently reverses epigenetic, transcriptional, synaptic plasticity, and behavioral deficits associated with Alzheimer's disease lesions in mice.