A molecular mechanism by which amyloid-β induces inactivation of CREB in Alzheimer’s Disease

Abstract

AbstractDisruption 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 Alzheimer’s disease (AD). CREB shut-off results in early synaptic dysfunction, contributes to AD pathology and eventually neuronal cell death and is elicited by amyloid-β (Aβ)-induced activation of extrasynaptic N-methyl-D-aspartate-receptors (NMDAR). In previous work we found that the protein messenger Jacob encodes and transduces the synaptic or extrasynaptic origin of NMDAR signals to the nucleus. In response to cell survival and plasticity-related synaptic NMDAR stimulation macromolecular transport of Jacob from synapse-to-nucleus docks the MAP-kinase ERK to the CREB complex which results in sustained CREB phosphorylation. Following disease-related activation of extrasynaptic NMDAR by Aβ 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) distinguishes extrasynaptic from synaptic NMDAR signaling and determines the affinity for the association with PP1γ. This mechanism contributes to transcriptional inactivation of CREB in the context of early synaptic dysfunction and cell loss in AD. Accordingly, Jacob protein knockdown attenuates Aβ-induced CREB shut-off and Jacob gene knockout is neuroprotective in a transgenic mouse model of AD. Collectively the data suggest that long-distance protein transport from NMDAR to the nucleus is part of early AD pathology and that Jacob docks a signalosome to CREB that is instrumental for CREB shut-off.