Deconstructing insulin in the brain

在对小鼠胰岛素进行全脑原位杂交后，我们发现小鼠脉络膜丛（Choroid Plexus， CP）中存在胰岛素的mRNA和蛋白表达。令人惊讶的是，它只在脑脊液中很容易被检测到，而在大脑的其他区域则没有。我们还发现，3XTg组年轻雌性小鼠的CP中胰岛素mRNA水平低于同龄对照组（图1B）。CP的差异基因表达分析也证实了这一说法，因为与分泌和钙信号相关的基因本体的变化得到了证实。因此，我们假设CP分泌功能，包括胰岛素分泌，在阿尔茨海默病病理过程的早期阶段发生改变。我们现在的策略是研究CP中的钙信号（胰岛素分泌需要钙信号），特别是IP3受体从内质网动员细胞内钙，因为它可能在动物模型的早期受到不利影响，这反过来会改变整个分泌组，而不仅仅是胰岛素。我们也在量化APP/PS1和野生型小鼠脉络膜丛中产生的其他激素的水平，我们将进行蛋白质组学研究，以建立AD前场状态下的分泌谱。CP中大量胰岛素的发现令人兴奋，出乎意料，开辟了CP研究的整个领域，特别是与衰老和AD有关的研究。因此胰岛素可能从两个来源影响胰岛素的作用：cp源性胰岛素和胰源性胰岛素。

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.