THE SERINE-THREONINE KINASE NDR2 IMPAIRS SPATIAL MEMORY THROUGH AN INTERPLAY OF AUTOPHAGY AND PROTEOSTASIS IN OF THE AGEING HIPPOCAMPUS

Aging evolves through the natural selection of a few antagonistic pleiotropic genes; these genes benefit early life but contribute to decline in later stages by affecting a wide range of processes. In the brain, these include gradual cognitive decline, altered neuronal connectivity, changes in synaptic activity, disruptions in proteostasis and autophagy, and increased neuroinflammation, among others. However, only a few genes that affect such a broad range of features in the brain have been identified, making them valuable targets for therapeutic interventions aimed at alleviating cognitive aging.
Ndr2 is a serine-threonine kinase involved in numerous neuronal functions. Previous work from our group demonstrated that Ndr2 participates in spatial memory, long-term potentiation, and spine formation. Moreover, Ndr2 also regulates autophagy, cell cycle regulation, inflammation, and intercellular communication. This suggests that Ndr2 may be an important factor in aging, particularly in the central nervous system.
In this study, we demonstrate that knocking down Ndr2 in aged mice impairs hippocampal autophagic flux, prevents age-related memory decline, and induces changes in the hippocampal proteome. We show that Ndr2 drives neuronal dysfunction through two main processes by increasing neuroinflammation and disrupting synaptic maintenance. Mechanistically, we show that Ndr2 increases autophagosome build-up at synapses and alters autophagic-lysosomal integrity. A meta-analysis revealed that Ndr2 favours the upregulation of a protein network associated with age-related and pathological cognitive decline.
These findings show that Ndr2 is an important modulator of brain aging and cognitive decline, positioning it as a promising target for interventions aimed at slowing age-related neurodegeneration.