Insulin and Insulin-Like Growth Factor Signaling Mechanisms in the Brain in Health and Disease

Impaired insulin action in the brain has been implicated in several neurological disorders, including Alzheimer’s disease (AD). AD is characterized by neuronal and hippocampal volume loss, dysregulation of brain energetics, and insulin resistance not unlike that seen with type 2 diabetes. Notably, AD brains demonstrate resistance to both insulin and insulin-like growth factors (IGF). Insulin and IGF signaling pathways are highly interrelated, but a full understanding of the degree to which each is impaired in AD and how reduced insulin/IGF signaling contributes to neurodegeneration remains elusive.
Here, we used a novel strategy to cross mice with knockout of neuronal insulin receptors in brain to a commonly utilized mouse model of AD and investigated the impact of the resulting reduced brain insulin signaling on AD phenotypes through behavioral and immunofluorescence studies. These studies present a mixed picture of the impact of neuronal insulin receptor deletion on AD pathology, including both exacerbating and ameliorating effects. Overall, these results highlight the need for continued research into the differential and overlapping effects of insulin, IGF1, and IGF2 signaling disruptions in the brain and their relation to neurodegenerative diseases.
We also proposed that a recently described protein, termed Inceptor, may play a role in brain insulin and IGF1 resistance. We studied Inceptor in healthy and diseased nervous tissue to understand the distribution of the protein and examine how it may change in states of insulin resistance. We found that Inceptor is in fact present in cerebellum, hippocampus, hypothalamus, and cortex of the brain in neurons, with higher levels in cortex of female compared to male mice. We also confirmed that Inceptor colocalized with IR and IGF1R in brain. We saw little difference in insulin receptor signaling following Inceptor knockdown in neuron cultures, or in Inceptor levels with high-fat diet in mouse or Alzheimer’s disease in mouse or human tissue. These results all provide significant advancements to our understanding of Inceptor in the brain.