Differential responses of primary neuron-secreted MCP-1 and IL-9 to type 2 diabetes and Alzheimer's disease-associated metabolites.
Differential responses of primary neuron-secreted MCP-1 and IL-9 to type 2 diabetes and Alzheimer's disease-associated metabolites.
复制标题
原代神经元分泌的 MCP-1 和 IL-9 对 2 型糖尿病和阿尔茨海默病相关代谢物的差异反应。
DOI：
10.1101/2023.11.17.567595
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Brubaker,DouglasK
中科院分区：
文献类型：
--
作者：
Ball,BrendanK;Kuhn,MadisonK;Fleeman,RebeccaM;Proctor,ElizabethA;Brubaker,DouglasK
2型糖尿病（T2 D）是阿尔茨海默病（AD）的危险因素，AD是最常见的痴呆形式。在这项工作中，我们研究了初级神经元对与AD、T2 D或两者相关的潜在循环、血脑屏障（BBB）可渗透代谢物的神经炎症反应。我们在文献中鉴定了与AD和T2 D的保护或有害性质相关的9种代谢物（月桂酸、天冬酰胺、果糖、花生四烯酸、氨基己二酸、山梨醇、视黄醇、色氨酸、烟酰胺），并在通过Luminex定量细胞因子分泌之前用每种代谢物刺激原代小鼠神经元培养物。我们采用无监督聚类，推理统计，偏最小二乘判别分析，以确定细胞因子浓度和代谢产物的疾病协会之间的关系。我们鉴定了MCP-1，一种与单核细胞募集相关的细胞因子，在与AD和T2 D的保护性和有害性相关的代谢物刺激的神经元之间差异丰富。我们还鉴定了IL-9，一种促进肥大细胞生长的细胞因子，与T2 D差异相关。事实上，响应于与T2 D相关的BBB可渗透代谢物而从神经元释放的细胞因子（诸如MCP-1和IL-9）可能通过神经炎症的下游效应而促进AD的发展。
Type 2 diabetes (T2D) is implicated as a risk factor for Alzheimer’s disease (AD), the most common form of dementia. In this work, we investigated neuroinflammatory responses of primary neurons to potentially circulating, blood–brain barrier (BBB) permeable metabolites associated with AD, T2D, or both. We identified nine metabolites associated with protective or detrimental properties of AD and T2D in literature (lauric acid, asparagine, fructose, arachidonic acid, aminoadipic acid, sorbitol, retinol, tryptophan, niacinamide) and stimulated primary mouse neuron cultures with each metabolite before quantifying cytokine secretion via Luminex. We employed unsupervised clustering, inferential statistics, and partial least squares discriminant analysis to identify relationships between cytokine concentration and disease-associations of metabolites. We identified MCP-1, a cytokine associated with monocyte recruitment, as differentially abundant between neurons stimulated by metabolites associated with protective and detrimental properties of AD and T2D. We also identified IL-9, a cytokine that promotes mast cell growth, to be differentially associated with T2D. Indeed, cytokines, such as MCP-1 and IL-9, released from neurons in response to BBB-permeable metabolites associated with T2D may contribute to AD development by downstream effects of neuroinflammation.