Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator

Chatterjee, Snehajyoti; Cassel, Raphaelle; Schneider‐Anthony, Anne; Mérienne, Karine; Cosquer, Brigitte; Tzeplaeff, Laura; Sinha, Sarmistha; Kumar, Manoj; Chaturbedy, Piyush; Eswaramoorthy, M.; Gras, Stéphanie Le; Keime, Céline; Bousiges, Olivier; Dutar, P.; Petsophonsakul, Petnoï; Rampon, Claire; Cassel, Jean‐Christophe; Buée, Luc; Blum, David; Kundu, Tapas K.; Boutillier, Anne‐Laurence

doi:10.15252/emmm.201708587

Cited by 66 publications

(61 citation statements)

References 86 publications

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“…Our RNA-Seq results from the WT group comparison (learning versus homecage) supports the present literature that learning induces CREB and CREM target genes that both interact with CBP for its transactivation (12,78,79). Among the CREB downstream genes, we found several activity-dependent genes (such as Arc, Egr1, Fos, Nr4a1, JunB) that previously have been shown upregulated following hippocampus-dependent learning (31,80,81). It is noteworthy that some of these activity-dependent genes were downregulated in CBP KIX/KIX mice, including Nr4a1.…”

Section: Discussionmentioning

confidence: 60%

“…Reducing Nr4A function in the hippocampus impairs long-term memory (82)(83)(84), while the activation of Nr4A family transcription factors enhances memory in young (85) and aged mice (86,87). Pharmacological activation of CBP in a mouse model of Alzheimer's disease rescues Nr4A gene expression and long-term memory (31).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, CBP functions as a histone acetyltransferase impacting gene expression during memory consolidation (22)(23)(24)(25)(26)(27), and more specifically in memory encoding in the medial prefrontal cortex (26,28). While restoring CREB activity in the CA1 of the dorsal hippocampus enables recovery from spatial memory deficits in an amyloid beta model of Alzheimer's disease (29), pharmacological activation of CBP/p300 HAT function also improves spatial learning in wildtype (WT) mice and restores spatial long-term memory retention and hippocampal plasticity in a tauopathy mouse model (30,31). Decreased levels or dysregulation of CBP have also been associated with neurodegenerative diseases including Huntington's Disease (32,33) and Alzheimer's disease (34)(35)(36).…”

Section: Introductionmentioning

confidence: 99%

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The CBP KIX domain regulates long-term memory and circadian activity

Chatterjee

Angelakos

Bahl

et al. 2020

Preprint

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CREB-dependent transcription necessary for long-term memory is driven by interactions with CREB-binding protein (CBP), a multi-domain protein that binds numerous transcription factors. Identifying specific domain functions for multi-action proteins is essential to understand processes necessary for healthy living including cognitive function and a robust circadian clock. We investigated the function of the CBP KIX domain in hippocampal memory and gene expression using CBP KIX/KIX mice with mutations that prevent phospho-CREB (Ser133) binding. We found that CBP KIX/KIX mice were impaired in long-term, but not short-term spatial memory in the Morris water maze. Using an unbiased analysis of gene expression after training for hippocampus-dependent memory, we discovered dysregulation of CREB and CLOCK target genes and downregulation of circadian genes in CBP KIX/KIX mice.With our finding that the CBP KIX domain was important for transcription of circadian genes, we profiled circadian activity in CBP KIX/KIX mice. CBP KIX/KIX mice exhibited delayed activity peaks after light offset and longer free-running periods in constant dark, although phase resetting to light was comparable to wildtype. These studies provide insight into the significance of the CBP KIX domain by defining targets of CBP transcriptional co-activation in memory and the role of the CBP KIX domain in vivo on circadian rhythms.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The CBP KIX domain regulates long-term memory and circadian activity

Chatterjee

Angelakos

Bahl

et al. 2020

Preprint

Self Cite

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“…It was recently reported that p300-mediated acetylation of beclin 1, VPS34, and SIK2 inhibits autophagy initiation, autophagosome maturation, and endocytic trafficking [34,52,53], suggesting that these proteins may play a role in regulating secretion of tau and potentially other proteins. Secondly, as p300/CBP regulates histone acetylation, the mechanism could also involve epigenetic changes in the autophagyrelevant transcriptome and synaptic plasticity [21,54,55]. Finally, acetylation of tau itself by p300/CBP increases tau toxicity, which could lead to cell damage such as impaired cytoskeleton stability and membrane integrity, and in turn contribute to elevated secretion.…”

Section: Discussionmentioning

confidence: 99%

“…However, it remains to be determined whether p300/CBP affects posttranslational modification of transmitted tau species, or tau seed uptake. In addition, p300/CBP's other effects on neurons [21], including neuronal plasticity [55,67] could also indirectly contribute to modulation of tau spreading. Finally, glial cells may contribute to tau spreading [68], and the p300/CBP-autophagy pathway could also be involved in these cells.…”

Section: Discussionmentioning

confidence: 99%

Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy

Chen

Wang

et al. 2020

Mol Neurodegeneration

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Background: The trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. There is critical knowledge gap in understanding how tau is released and transmitted, and how that is dysregulated in diseases. Previously, we reported that lysine acetyltransferase p300/CBP acetylates tau and regulates its degradation and toxicity. However, whether p300/CBP is involved in regulation of tau secretion and propagation is unknown. Method: We investigated the relationship between p300/CBP activity, the autophagy-lysosomal pathway (ALP) and tau secretion in mouse models of tauopathy and in cultured rodent and human neurons. Through a high-through-put compound screen, we identified a new p300 inhibitor that promotes autophagic flux and reduces tau secretion. Using fibril-induced tau spreading models in vitro and in vivo, we examined how p300/CBP regulates tau propagation. Results: Increased p300/CBP activity was associated with aberrant accumulation of ALP markers in a tau transgenic mouse model. p300/CBP hyperactivation blocked autophagic flux and increased tau secretion in neurons. Conversely, inhibiting p300/CBP promoted autophagic flux, reduced tau secretion, and reduced tau propagation in fibril-induced tau spreading models in vitro and in vivo. Conclusions: We report that p300/CBP, a lysine acetyltransferase aberrantly activated in tauopathies, causes impairment in ALP, leading to excess tau secretion. This effect, together with increased intracellular tau accumulation, contributes to enhanced spreading of tau. Our findings suggest that inhibition of p300/CBP as a novel approach to correct ALP dysfunction and block disease progression in tauopathy.

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Extracellular matrix stiffness controls cardiac valve myofibroblast activation through epigenetic remodeling

Walker

Batan

Bishop

et al. 2022

Bioengineering & Transla Med

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Aortic valve stenosis (AVS) is a progressive fibrotic disease that is caused by thickening and stiffening of valve leaflets. At the cellular level, quiescent valve interstitial cells (qVICs) activate to myofibroblasts (aVICs) that persist within the valve tissue.Given the persistence of myofibroblasts in AVS, epigenetic mechanisms have been implicated. Here, we studied changes that occur in VICs during myofibroblast activation by using a hydrogel matrix to recapitulate different stiffnesses in the valve leaflet during fibrosis. We first compared the chromatin landscape of qVICs cultured on soft hydrogels and aVICs cultured on stiff hydrogels, representing the native and diseased phenotypes respectively. Using assay for transposase-accessible chromatin sequencing (ATAC-Seq), we found that open chromatin regions in aVICs were enriched for transcription factor binding motifs associated with mechanosensing pathways compared to qVICs. Next, we used RNA-Seq to show that the open chromatin regions in aVICs correlated with pro-fibrotic gene expression, as aVICs expressed higher levels of contractile fiber genes, including myofibroblast markers such as alpha smooth muscle actin (αSMA), compared to qVICs. In contrast, chromatin remodeling genes were downregulated in aVICs compared to qVICs, indicating qVICs may be protected from myofibroblast activation through epigenetic mechanisms. Small molecule inhibition of one of these remodelers, CREB Binding Protein (CREBBP), prevented qVICs from activating to aVICs. Notably, CREBBP is more abundant in valves from healthy Cierra J. Walker and Dilara Batan have contributed equally to this study.

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Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator

Cited by 66 publications

References 86 publications

The CBP KIX domain regulates long-term memory and circadian activity

The CBP KIX domain regulates long-term memory and circadian activity

Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy

Extracellular matrix stiffness controls cardiac valve myofibroblast activation through epigenetic remodeling

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