PDF(Pubmed)
Abstract：
BACKGROUND: Aberrant neuronal Sigma-1 receptor (Sig-1r)-mediated endoplasmic reticulum (ER)- mitochondria signaling plays a key role in the neuronal cytopathology of Alzheimer\'s disease (AD). The natural psychedelic N, N-dimethyltryptamine (DMT) is a Sig-1r agonist that may have the anti-AD potential through protecting neuronal ER-mitochondrial interplay.
METHODS: 3×TG-AD transgenic mice were administered with chronic DMT (2 mg/kg) for 3 weeks and then performed water maze test. The Aβ accumulation in the mice brain were determined. The Sig-1r level upon DMT treatment was tested. The effect of DMT on the ER-mitochondrial contacts site and multiple mitochondria-associated membrane (MAM)-associated proteins were examined. The effect of DMT on calcium transport between ER and mitochondria and the mitochondrial function were also evaluated.
RESULTS: chronic DMT (2 mg/kg) markedly alleviated cognitive impairment of 3×TG-AD mice. In parallel, it largely diminished Aβ accumulation in the hippocampus and prefrontal cortex. DMT restored the decreased Sig-1r levels of 3×TG-AD transgenic mice. The hallucinogen reinstated the expression of multiple MAM-associated proteins in the brain of 3×TG-AD mice. DMT also prevented physical contact and calcium dynamic between the two organelles in in vitro and in vivo pathological circumstances. DMT modulated oxidative phosphorylation (OXPHOS) and ATP synthase in the in vitro model of AD.
CONCLUSIONS: The anti-AD effects of DMT are associated with its protection of neuronal ER-mitochondria crosstalk via the activation of Sig-1r. DMT has the potential to serve as a novel preventive and therapeutic agent against AD.
METHODS: 3×TG-AD transgenic mice were administered with chronic DMT (2 mg/kg) for 3 weeks and then performed water maze test. The Aβ accumulation in the mice brain were determined. The Sig-1r level upon DMT treatment was tested. The effect of DMT on the ER-mitochondrial contacts site and multiple mitochondria-associated membrane (MAM)-associated proteins were examined. The effect of DMT on calcium transport between ER and mitochondria and the mitochondrial function were also evaluated.
RESULTS: chronic DMT (2 mg/kg) markedly alleviated cognitive impairment of 3×TG-AD mice. In parallel, it largely diminished Aβ accumulation in the hippocampus and prefrontal cortex. DMT restored the decreased Sig-1r levels of 3×TG-AD transgenic mice. The hallucinogen reinstated the expression of multiple MAM-associated proteins in the brain of 3×TG-AD mice. DMT also prevented physical contact and calcium dynamic between the two organelles in in vitro and in vivo pathological circumstances. DMT modulated oxidative phosphorylation (OXPHOS) and ATP synthase in the in vitro model of AD.
CONCLUSIONS: The anti-AD effects of DMT are associated with its protection of neuronal ER-mitochondria crosstalk via the activation of Sig-1r. DMT has the potential to serve as a novel preventive and therapeutic agent against AD.
摘要：
背景：异常神经元Sigma-1受体（Sig-1r）介导的内质网（ER）-线粒体信号在阿尔茨海默病（AD）的神经元细胞病理学中起关键作用。自然的迷幻N，N-二甲基色胺(DMT)是Sig-1r激动剂,其可通过保护神经元ER-线粒体相互作用而具有抗AD潜能。
方法:3xTG-AD转基因小鼠给予慢性DMT(2mg/kg)3周,然后进行水迷宫试验。测定小鼠脑中的Aβ积累。测试DMT处理后的Sig-1r水平。检查了DMT对ER-线粒体接触位点和多个线粒体相关膜（MAM）相关蛋白的影响。还评估了DMT对ER和线粒体之间的钙转运和线粒体功能的影响。
结果：慢性DMT（2mg/kg）可明显减轻3×TG-AD小鼠的认知障碍。并行,它大大减少了海马和前额叶皮层中Aβ的积累。DMT恢复了3×TG-AD转基因小鼠的降低的Sig-1r水平。致幻剂可恢复3×TG-AD小鼠脑中多种MAM相关蛋白的表达。DMT还在体外和体内病理情况下阻止了两种细胞器之间的物理接触和钙动力。DMT在AD的体外模型中调节氧化磷酸化（OXPHOS）和ATP合酶。
结论：DMT的抗AD作用与其通过激活Sig-1r保护神经元ER-线粒体串扰有关。DMT具有作为抗AD的新型预防和治疗剂的潜力。
方法:3xTG-AD转基因小鼠给予慢性DMT(2mg/kg)3周,然后进行水迷宫试验。测定小鼠脑中的Aβ积累。测试DMT处理后的Sig-1r水平。检查了DMT对ER-线粒体接触位点和多个线粒体相关膜（MAM）相关蛋白的影响。还评估了DMT对ER和线粒体之间的钙转运和线粒体功能的影响。
结果：慢性DMT（2mg/kg）可明显减轻3×TG-AD小鼠的认知障碍。并行,它大大减少了海马和前额叶皮层中Aβ的积累。DMT恢复了3×TG-AD转基因小鼠的降低的Sig-1r水平。致幻剂可恢复3×TG-AD小鼠脑中多种MAM相关蛋白的表达。DMT还在体外和体内病理情况下阻止了两种细胞器之间的物理接触和钙动力。DMT在AD的体外模型中调节氧化磷酸化（OXPHOS）和ATP合酶。
结论：DMT的抗AD作用与其通过激活Sig-1r保护神经元ER-线粒体串扰有关。DMT具有作为抗AD的新型预防和治疗剂的潜力。
