Endocrine Abstracts

Older population and people with type II diabetes have a significantly higher rate of decline in cognitive function. However, the mechanisms are poorly understood. There are strong links between insulin and cognitive function supported by epidemiological data from humans and animal studies and in vitro research. Protein kinase C (PKC) signaling cascades and insulin pathways are closely integrated. The consequences of PKC activation by insulin in the CNS influence memory, cognition, synaptogenesis, and neuronal repair. In addition, PKCδ, a novel PKC has been implicated in memory, neuronal survival and proliferation. Insulin regulates the alternative splicing of mouse PKCδ splice variants: PKCδI promotes apoptosis while PKCδII functions as pro-survival protein. In vitro and in vivo studies demonstrated that apoptosis accounted for the neuronal loss and cognitive decline in the aging and diabetic mouse models. Our in vivo data demonstrates that intranasal insulin improves memory and cognition in aging and diabetic mice. Our in vivo data in mouse neural cells derived from the hippocampus, which is the seat of learning, memory and cognition, demonstrates that insulin increases the expression of PKCδII. PKCδII expression is not influenced by high glucose or thiazolidinediones thereby establishing that insulin increases PKCδII expression via its signaling pathways. To determine which pathways are involved in insulin-mediated PKCδ alternative splicing in neuronal cells, we used inhibitors of several pathways targeted by insulin in other tissues and show that insulin increases PKCδII expression via PI3K-Akt pathway. Constitutively active Akt2 kinase mimicked insulin effects in increasing PKCδII levels while WT-Akt2 kinase had no effect without insulin. Further, we show that PKCδII increases expression of pro-survival proteins Bcl-2 and Bcl-xL thereby increasing neurogenesis. In conclusion, we demonstrate that insulin improves cognitive functions via PKCδ.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.