Ceramide Signaling in AD Pathogenesis

项目总结 最近的证据表明，阿尔茨海默病(AD)在病因学上与许多 代谢紊乱，包括具有共同病理过程的2型糖尿病(T2 DM) 包括线粒体功能障碍和胰岛素抵抗(IR)。关于机制 在T2 DM相关的全身性IR的基础上，有压倒性证据表明神经酰胺的作用 (CER)，特别是C16-Cer，由改变的鞘脂(SPL)代谢产生。我们的 初步研究表明，这种神经酰胺的水平随着这种酶的增加而增加 在AD小鼠模型的海马区产生它，即神经酰胺合成酶-6(CerS6)， PDAPP TG(J-20)和2型糖尿病野生型小鼠。这些变化伴随着增加的 1-磷酸鞘氨醇(S1P)水平，从而表明AD患者的Cer/S1P变阻器发生改变。 在这个项目中，我们将检验CerS6/C16-Cer上调与 阿尔茨海默病患者的脑IR和线粒体功能障碍，阻断这一通路可减轻AD 病理学和相关的认知障碍。此外，我们还将测试 ‘Cer/S1P变阻器’下游的脂肪因子受体，即由脂联素激活的AdipoR (APN)，已知可以对抗代谢紊乱中的IR，也可以减轻AD的病理 在小鼠模型中。为了实现这些探索性目标，我们将使用两个鼠标模型 AD，即PDAPP TG(J-20)和5xFAD。转基因小鼠将与CerS6基因敲除的小鼠杂交 小鼠或给予CerS6反义寡核苷酸(Aim 1)或给予APN激动剂， AdipoRon(已知激活神经酰胺酶并将Cer转化为S1P的APN- 介导的信号通路)，神经酰胺酶缺失或不缺失(目标2)。 这种SPL病理生物学方法(一个未被研究的领域)不仅有助于获得基本的 从以代谢为中心的新视角理解AD的发病机制 基于脂质信号的治疗AD的策略。

Project summary Recent evidence shows that Alzheimer’s disease (AD) has etiological links to a number of metabolic disorders including type-2 diabetes (T2DM) with shared pathological processes including mitochondrial dysfunction and insulin resistance (IR). With respect to mechanisms underlying T2DM-associated systemic IR, there is overwhelming evidence for the role of ceramide (Cer), in particular C16-Cer generated from altered sphingolipid (SPL) metabolism. Our preliminary studies show increased levels of this ceramide species along with the enzyme that produces it i.e., ceramide synthase-6 (CerS6) in the hippocampus of a mouse model of AD, PDAPP Tg (J-20) as well as type-2 diabetic wild-type mice. These changes accompany increased levels of sphingosine 1-phosphate (S1P) thereby indicating an altered ‘Cer/S1P rheostat’ in AD. In this project, we will test the hypothesis that CerS6/C16-Cer upregulation is associated with brain IR and mitochondrial dysfunction in AD so that a blockade of this pathway will attenuate AD pathology and associated cognitive impairment. In addition, we will test the significance of ‘Cer/S1P rheostat’ down-stream of an adipokine receptor i.e., AdipoR activated by adiponectin (APN), which is known to counter IR in metabolic disorders and also to attenuate AD pathology in mouse models. To accomplish these exploratory objectives, we will use two mouse models of AD i.e., PDAPP Tg (J-20) and 5xFAD. The transgenic mice will be crossed with CerS6 knockout mice or administered CerS6 antisense oligonucleotides (Aim 1) or administered an APN agonist, AdipoRon (which is known to activate ceramidase and convert Cer into S1P as one of APN- mediated signaling pathways) with or without ceramidase deletion (Aim 2). This SPL pathobiology approach (an understudied area) will not only help gain a basic understanding of AD pathogenesis from a novel metabolism-centric perspective but also suggest lipid signaling based therapeutic strategies to treat AD.