Deconstructing insulin in the brain

解构大脑中的胰岛素

• 批准号: 10688804
• 负责人: Josephine Egan
• 金额: $ 27.91万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688804
• 关键词: 3xTg-AD mouse; APP-PS1; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid deposition; Animal Model; Area; Behavior; Blood Glucose; Brain; CB1 knockout; Calcium; Calcium Signaling; Calories; Cells; Cerebrum; Data Collection; Diabetes Mellitus; Diet; Endoplasmic Reticulum; Female; Gene Expression Profiling; Genes; Hormones; Human; Hyperglycemia; Hyperinsulinism; Hyperlipidemia; Hypoglycemia; In Situ Hybridization; Insulin; Insulin Receptor; Insulin Resistance; Lead; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Mus; Neurons; Ontology; Pancreas; Pathologic Processes; Pathway interactions; Peripheral; Phenotype; Proteins; Proteomics; Structure of choroid plexus; Testing; Tissue-Specific Gene Expression; Wild Type Mouse; experimental study; insulin secretion; insulin signaling; mouse model; novel; prevent; receptor

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.

最初对小鼠胰岛素进行全脑原位杂交后，我们发现小鼠脉络丛（CP）中存在胰岛素表达（mRNA和蛋白质）。令人惊讶的是，它仅在 CP 中很容易检测到，而在其他大脑区域中则没有。我们还发现，与年龄匹配的对照同窝小鼠相比，3XTg 小鼠中年轻雌性小鼠的 CP 中胰岛素 mRNA 水平较低（图 1B）。他们的 CP 中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传导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 中的钙信号传导（胰岛素分泌需要钙信号传导），特别是 IP3 受体从内质网动员细胞内钙，因为它可能在该动物模型的早期受到不利影响，并且这反过来会改变整个分泌组，而不仅仅是胰岛素。我们还量化了 APP/PS1 和野生型小鼠脉络丛中已知产生的其他激素的水平，并且我们将进行蛋白质组学，以建立前驱 AD 状态下的分泌谱。 CP 中富含胰岛素这一令人兴奋的发现是出乎意料的，并且开启了 CP 研究的整个领域，尤其是衰老和 AD 方面的研究。因此，胰岛素可能通过两个来源影响胰岛素的作用：CP 来源的胰岛素和胰腺来源的胰岛素。