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

Area of Science:

• Neuroscience
• Endocrinology
• Molecular Biology

Background:

• Insulin resistance and impaired insulin signaling are linked to Alzheimer's disease (AD) pathogenesis.
• Brain insulin receptor (IR) activation enhances neural resilience, cognition, and learning.
• IR splice variants (IR-A and IR-B) may influence insulin resistance.

Purpose of the Study:

• To investigate the distribution and specificity of IR beta subunit antibodies in human brain tissue.
• To quantify the expression of IR-A and IR-B isoforms in neurons of the entorhinal cortex (EC) and middle temporal gyrus (MTG) in normal aging and AD.
• To explore the role of IR isoforms in brain insulin resistance and AD.

Main Methods:

• Immunohistochemistry using IR beta subunit antibodies on post-mortem human brain tissue.
• RNAscope in situ hybridization to identify and quantify IR-A and IR-B mRNA in neurons.
• Analysis of tissue from aged normal and AD individuals in the EC and MTG.

Main Results:

• IR beta subunit immunoreactivity was observed in neurons and astrocytes, but not other glial cells.
• Both IR-A and IR-B mRNA isoforms were abundant in neurons in both normal and AD brains.
• The IR-B (Exon 11+) isoform was predominant in the EC of AD brains compared to controls.

Conclusions:

• The study identified neuronal expression of IR isoforms and characterized IR antibody binding in the human brain.
• Predominance of the IR-B isoform in the AD entorhinal cortex suggests a potential compensatory response to brain insulin resistance.
• These findings contribute to understanding the molecular mechanisms underlying brain insulin resistance in Alzheimer's disease.