CLINICAL PROJECT: Deconstructing insulin in the brain

National Institute On Aging

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Abstract

After initially carried out whole brain in situ hybridization for insulin in mouse, and we found that insulin expression (both mRNA and protein) in present in the Choroid Plexus (CP) of mice. Surprisingly, it was easily detectable in only CP, and no any other brain area. We also found lower insulin mRNA levels in the CP of young females in the 3XTg mice when compared to their age-matched control littermates (figure 1B). Differential gene expression analysis in their CP also substantiated this statement, as changes in gene ontology associated with the secretory and calcium signaling were confirmed. Therefore, we hypothesize that the CP secretory function, including insulin secretion, is altered in early stages of the Alzheimers disease pathological process. Our strategy now is to investigate calcium signaling in the CP (calcium signaling is required for insulin secretion) particularly the mobilization of intracellular calcium from the endoplasmic reticulum by IP3 receptors, as it likely is adversely affected in early ages of this animal model, and this in turn would alter the secretome in its entirety and not just insulin. We are also quantifying levels of other hormones known to be produced in the choroid plexus of APP/PS1 and wild type mice and we will carry out proteomics in order to build a secretory profile in the prodomal AD state. The exciting finding of abundant insulin in CP was unexpected and has opened a whole area of CP study, especially with aging and AD. So insulin is likely influencing insulin action from two sourcesCP-derived and pancreas-derived insulin.