Preventing Jacob-induced transcriptional inactivation of CREB protects synapses from β-amyloid in Alzheimer's Disease

Katarzyna M. Grochowska; Guilherme M. Gomes; Rajeev Raman; Rahul Kaushik; Liudmila Sosulina; Hiroshi Kaneko; Anja Maria Oelschlegel; PingAn Yuanxiang; Irene Reyes‐Resina; Gonca Bayraktar; Sebastian Samer; Christina Spilker; Marcel S. Woo; Markus Morawski; Jürgen Goldschmidt; Manuel Alexander Friese; Steffen Roßner; Gemma Navarro; Stefan Remy; Carsten Reißner; Anna Karpova; Michael R. Kreutz

doi:10.15252/embj.2022112453

NeuroscienceThe EMBO JournalJan 3, 2023

Peer-reviewed journal article

Preventing Jacob-induced transcriptional inactivation of CREB protects synapses from β-amyloid in Alzheimer's Disease

Katarzyna M. Grochowska iD, Guilherme M. Gomes iD, Rajeev Raman iD, Rahul Kaushik iD, Liudmila Sosulina, Hiroshi Kaneko iD, Anja Maria Oelschlegel iD, PingAn Yuanxiang iD, Irene Reyes‐Resina iD, Gonca Bayraktar iD, Sebastian Samer iD, Christina Spilker iD, Marcel S. Woo iD, Markus Morawski iD, Jürgen Goldschmidt iD, Manuel Alexander Friese iD, Steffen Roßner iD, Gemma Navarro iD, Stefan Remy iD, Carsten Reißner iD, Anna Karpova iD, Michael R. Kreutz iD

Abstract

Synaptic dysfunction caused by soluble {beta}-Amyloid (A{beta}) is a hallmark of the early stage of Alzheimers disease (AD) and is tightly linked to cognitive decline. A{beta} induces by yet unknown mechanisms disruption of transcriptional activity of cAMP- responsive element-binding protein (CREB), a master regulator of cell survival and plasticity-related gene expression. Here, we report that A{beta} elicits cytonuclear trafficking of Jacob, a protein serves as a mobile signaling hub that docks a signalosome to CREB, which induces transcriptional inactivation and subsequent synapse impairment and eventually loss in AD. The small chemical compound Nitarsone selectively hinders assembly of this signalosome and thereby restores CREB transcriptional activity. Nitarsone prevents impairment of synaptic plasticity as well as cognitive decline in mouse models of AD. Collectively, the data suggest that targeting Jacob induced CREB shutoff is a therapeutic avenue against early synaptic dysfunction in AD.

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