Abstract
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.
Footnotes
In the previous version of the manuscript, we described molecular mechanism linked to transcriptional inactivation and subsequent synapse impairment and loss in Alzheimer's disease (AD). In the revised version we further demonstrate the relevance of the identified mechanism for early synaptic failure in AD by targeting a crucial protein interaction responsible for CREB shutoff with the small chemical compound Nitarsone. The new data suggest that this pathway provides novel molecular entry points for AD-relevant interventions.
