Insulin Receptor Isoform Pattern in Aged Normal and Alzheimer's Human Cortex

Desensitisation to insulin nearly doubles the risk of developing Alzheimer's disease (AD), a degenerative brain disorder and the leading cause of dementia. Impairment of the insulin signalling pathway is also apparent in AD brain tissue even in the absence of body-wide insulin resistance. Activation of the insulin receptor (IR) in the brain increases neural resilience by promoting structural and synaptic plasticity, glucose metabolism, and resistance to apoptosis, thereby enhancing cognition and learning. Additionally, the splice variants of IR have differing downstream effects, and their ratio may play a role in insulin resistance. I n this work, the immunolabelling pattern and binding specificity of a range of IR beta subunit (IRβ) antibodies was studied in post-mortem human brain tissue. Immunoreactivity in brain tissue was observed on almost all neurons and some astrocytes, but no other glia. Further, isoforms of IR transcripts both with and without exon 11 (IR-B and IR-A respectively) were identified within neurons and quantified in situ in the aged normal and AD entorhinal cortex (EC) and middle temporal gyrus (MTG) using RNAscope. Our results demonstrate the mRNA for both isoforms were abundant in similar quantities. However, IR-B (Ex11⁺), the more efficient isoform, was predominant in the EC in AD, potentially reflecting a compensatory effect of brain insulin resistance.