Jacob‐induced transcriptional inactivation of CREB promotes Aβ‐induced synapse loss in Alzheimer's disease
Year: 2023
Type: article
Abstract: Synaptic dysfunction caused by soluble β-amyloid peptide (Aβ) is a hallmark of early-stage Alzheimer's disease (AD), and is tightly linked to cognitive decline. By yet unknown mechanisms, Aβ suppresses the transcriptional activity of cAMP-responsive element-binding protein (CREB), a master regulator of cell survival and plasticity-related gene expression. Here, we report that Aβ elicits nucleocytoplasmic trafficking of Jacob, a protein that connects a NMDA-receptor-derived signalosome to CREB, in AD patient brains and mouse hippocampal neurons. Aβ-regulated trafficking of Jacob induces transcriptional inactivation of CREB leading to impairment and loss of synapses in mouse models of AD. The small chemical compound Nitarsone selectively hinders the assembly of a Jacob/LIM-only 4 (LMO4)/ Protein phosphatase 1 (PP1) 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 targeting Jacob protein-induced CREB shutoff as a therapeutic avenue against early synaptic dysfunction in AD.
Source: The EMBO Journal
Authors: Katarzyna M Grochowska, Guilherme M Gomes, Rajeev Raman, Rahul Kaushik, Liudmila Sosulina, Hiroshi Kaneko, Anja M Oelschlegel, PingAn Yuanxiang, Irene Reyes‐Resina, Gonca Bayraktar, Sebastian Samer, Christina Spilker, Marcel S Woo, Markus Morawski, Jürgen Goldschmidt, Manuel A Friese, Steffen Rossner, Gemma Navarro, Stefan Remy, Carsten Reissner, Anna Karpova, Michael R Kreutz
Institutions: University Medical Center Hamburg-Eppendorf, Leibniz Institute for Neurobiology, Center for Behavioral Brain Sciences, Otto-von-Guericke-Universität Magdeburg, German Center for Neurodegenerative Diseases, Institute of Neuroimmunology and Multiple Sclerosis, Leipzig University, Universitat de Barcelona, University of Münster
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $6,100
OpenAlex ID: W4313455176