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

Abstract

Disruption of transcriptional activity of cAMP-responsive element-binding protein (CREB), a master regulator of cell survival and plasticity-related gene expression, is a hallmark of neurodegenerative diseases. CREB shut-off results in synaptic dysfunction and neuronal cell death and is elicited in Alzheimer's disease (AD) by amyloid-βinduced activation of extrasynaptic N-methyl-D-aspartate-receptors (NMDAR).Following long-distance transport from NMDAR to the nucleus the protein messenger Jacob docks a signalosome to CREB that encodes the synaptic or extrasynaptic origin of the NMDAR signal. In previous work we found that in response to cell survival/plasticity related synaptic NMDAR stimulation macromolecular transport of Jacob docks the MAP-kinase ERK to the CREB complex which results in sustained CREB phosphorylation. Here we show that in case of disease-related activation of extrasynaptic NMDAR by amyloid-β, Jacob associates with protein phosphatase-1γ (PP1γ) and induces dephosphorylation and transcriptional inactivation of CREB.Binding of the adaptor protein LIM domain only 4 (LMO4) to Jacob distinguishes extrasynaptic from synaptic NMDAR signaling and determines the affinity for the association with PP1γ. This mechanism contributes to transcriptional inactivation of CREB in response to extrasynaptic NMDAR signaling in the context of early synaptic dysfunction and cell loss in AD. Accordingly, Jacob protein knockdown attenuates CREB shut-off and cellular deterioration in response to amyloid-β signaling and Jacob gene knock out is neuroprotective in a transgenic mouse model of AD.

The nuclear lamina is a hub for the nuclear function of Jacob

“…At present, it is unclear whether plasticity-related gene expression regulated by nuclear Jacob will occur in such factories. However, the association of Jacob with CREB is not limited to membrane-proximal regions, [20] and we cannot exclude the possibility of a role of the protein in the opposite process, i.e. gene silencing.…”

“…One of these messengers is Jacob, a protein that encodes and transduces the synaptic and extrasynaptic origin of GluN2B NMDAR signals to the nucleus [15]. In the nucleus, Jacob docks a signalosome to the cAMP response element binding protein (CREB)-complex [20], however, little is known about its subnuclear localization and corresponding dynamics. In previous work employing immunocytochemical staining and confocal imaging, we observed that Jacob localizes to the nuclear rim in hippocampal neurons [14,16,21,22].…”

Jacob, a Synapto-Nuclear Protein Messenger Linking N-methyl-D-aspartate Receptor Activation to Nuclear Gene Expression

“…Of note, the direct interaction of Jacob with CREB does not depend on the phosphorylation of S180. In response to synaptic NMDAR activation, Jacob phosphorylated at S180 accumulates in the nucleus (Dieterich et al, 2008;Karpova et al, 2013;Spilker et al, 2016b;Grochowska et al, 2017) where it then binds CREB (Karpova et al, 2013;Grochowska et al, 2020).…”

“…Activation of extrasynaptic NMDARs leads to the formation and translocation of a different Jacob transport complex (Dieterich et al, 2008;Karpova et al, 2013;Grochowska et al, 2020). Several lines of evidence indicate that extrasynaptic NMDAR activity evoked by the block of synaptic NMDARs and subsequent treatment with NMDA induces dephosphorylation of ERK1/2 and Jacob (Figure 1.7; Ivanov et al, 2006;Rönicke et al, 2011;Karpova et al, 2013;Gomes et al, 2014;Grochowska et al, 2017;Grochowska et al, 2020) and triggers CREB shut-off resulting in synaptic dysfunction, synapse loss and subsequent cell death (Hardingham and Bading, 2010;Yan et al, 2020). Soluble amyloid-β oligomers (AβOs) are causative agents underlying the onset and progression of AD (Selkoe and Hardy, 2016;Cline et al, 2018).…”

“…Soluble amyloid-β oligomers (AβOs) are causative agents underlying the onset and progression of AD (Selkoe and Hardy, 2016;Cline et al, 2018). It was shown that different AβOs species, Aβ1-42 and Aβ25-35, act on extrasynaptic NMDARs and drive non-phosphorylated Jacob in the nucleus which triggers CREB shut-off (Figure 1.8; Rönicke et al, 2011;Gomes et al, 2014;Grochowska et al, 2017Grochowska et al, , 2020. Jacob seems to play a role in extrasynaptic NMDAR signaling linked to neurodegenerative disorders and interrupted CREB-dependent gene expression at the early stage of AD pathology (Rönicke et al, 2011;Gomes et al, 2014;Grochowska et al, 2017Grochowska et al, , 2020.…”