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

Synaptic dysfunction caused by soluble β-Amyloid (Aβ) is a hallmark of the early stage of Alzheimer’s disease (AD) and is tightly linked to cognitive decline. Aβ 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 Aβ 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. ### Competing Interest Statement KMG, GMG, AMO, AK, CR, and MRK are named inventors of the patent application No. EP22166017.