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.