Alzheimer’s Disease & Dementia

Insulin deficiency and insulin resistance has both been reported in Alzheimer’s disease. This study was designed to examine whether insulin protein or markers of insulin promoter activity can be observed in the mouse brain and to also determine the effects of brain-specific insulin gene (Ins2) knockout on behaviour to ascertain the possible role of insulin produced locally in the brain. We have employed germline Ins2 knockout mice (Ins2-/-), heterozygous mutant mice (Ins2+/-), and their wildtype littermate controls (Ins2+/+), as well as cell type specific Ins2 knockout mice derived by crossing NesCre, SynCre, or CamkCre mice with mice harboring a floxed Ins2 allele (on the Ins1-/- background). Mice were genotyped using PCR. Insulin mRNA analysis using qPCR confirmed the deletion of the Ins2 gene in the germline knockout animals, but revealed a paradoxical increase in Ins2 mRNA in many brain regions of the Ins1-/-:Ins2f/f:NesCre, Ins1-/-:Ins2f/f:SynCre, Ins1-/-:Ins2f/f:CamkCre, relative to their littermate controls, suggesting an upregulation of Ins2 production from non-neuronal cell types within the brain.

Indeed, analysis of Ins2 gene activity using Ins2GFP knock-in mice suggested the presence of Ins2 in non-neuronal cell types surrounding the ventricles. Interestingly, preliminary behavioural studies (Y-maze, open field test, familiar object test, and Morris water maze) identified differences in learning and memory in mice lacking Ins2 expression in the brain. Collectively, these results suggest that Ins2 is expressed in both neuronal and non-neuronal cell types within the brain, where it has complex roles modulating behavior. This work may shed light on the role of insulin in Alzheimer’s disease.