<br>抑制 tau 诱导的 nSMase2 活性升高和神经酰胺对阿尔茨海默病小鼠模型具有治疗作用,Translational Neurodegeneration

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抑制 tau 诱导的 nSMase2 活性升高和神经酰胺对阿尔茨海默病小鼠模型具有治疗作用
Translational Neurodegeneration ( IF 10.8 ) Pub Date : 2023-12-04 , DOI: 10.1186/s40035-023-00383-9
Carolyn Tallon _{1,

2} , Benjamin J Bell _{1,

2} , Medhinee M Malvankar ₁ , Pragney Deme ₂ , Carlos Nogueras-Ortiz ₃ , Erden Eren ₃ , Ajit G Thomas ₁ , Kristen R Hollinger ₁ , Arindom Pal _{1,

2} , Maja Mustapic ₃ , Meixiang Huang _{1,

2} , Kaleem Coleman _{1,

4} , Tawnjerae R Joe _{1,

4} , Rana Rais _{1,

2,

5} , Norman J Haughey _{2,

6,

7} , Dimitrios Kapogiannis _{2,

3} , Barbara S Slusher _{1,

2,

5,

6,

8,

9}

Affiliation

阿尔茨海默病 (AD) 的认知能力下降与神经元之间沿突触连接网络的过度磷酸化 tau (pTau) 传播有关，部分通过细胞外囊泡 (EV) 传播。 EV 生物发生是由中性鞘磷脂酶 2 (nSMase2) 介导的鞘磷脂裂解导致质膜上神经酰胺富集所触发。我们首次报告人类 tau 表达可提高大脑神经酰胺和 nSMase2 活性。为了确定抑制这种升高的治疗效果，我们在转基因 PS19 AD 小鼠模型中评估了 PDDC，这是第一个有效的、选择性的、口服生物可利用的、脑可渗透的 nSMase2 抑制剂。此外，我们直接评估了 PDDC 对小鼠模型中 tau 增殖的影响，其中将编码 P301L/S320F 双突变人类 tau 的腺相关病毒 (AAV) 单侧立体定位注射到海马体中。监测双突变人 tau 蛋白向齿状回的对侧转移。我们检查了从小鼠血浆中分离出的 EV 中的神经酰胺水平、组织病理学变化和 pTau 含量。与人类 AD 类似，PS19 小鼠表现出脑神经酰胺水平和 nSMase2 活性增加；通过 PDDC 治疗，两者均完全正常化。 PS19小鼠还表现出tau免疫染色升高、海马神经元细胞层变薄、苔藓纤维突触素免疫染色增加以及神经胶质细胞活化，所有这些都是人类AD的病理特征。 PDDC 治疗减少了这些变化。与未治疗的小鼠相比，经 PDDC 治疗的 PS19 小鼠血浆中神经元和小胶质细胞来源的 EV 水平降低，前者携带的 pTau 水平较低。在 tau 传播模型中，PDDC 使 tau 诱导的脑神经酰胺增加正常化，并显着减少 tau 向对侧传播的量。 PDDC 是一种一流的候选治疗药物，可以使升高的脑神经酰胺和 nSMase2 活性正常化，从而减缓 AD 小鼠中 tau 蛋白的扩散。

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Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model

Cognitive decline in Alzheimer’s disease (AD) is associated with hyperphosphorylated tau (pTau) propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EVs). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2 (nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that human tau expression elevates brain ceramides and nSMase2 activity. To determine the therapeutic benefit of inhibiting this elevation, we evaluated PDDC, the first potent, selective, orally bioavailable, and brain-penetrable nSMase2 inhibitor in the transgenic PS19 AD mouse model. Additionally, we directly evaluated the effect of PDDC on tau propagation in a mouse model where an adeno-associated virus (AAV) encoding P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus. The contralateral transfer of the double mutant human tau to the dentate gyrus was monitored. We examined ceramide levels, histopathological changes, and pTau content within EVs isolated from the mouse plasma. Similar to human AD, the PS19 mice exhibited increased brain ceramide levels and nSMase2 activity; both were completely normalized by PDDC treatment. The PS19 mice also exhibited elevated tau immunostaining, thinning of hippocampal neuronal cell layers, increased mossy fiber synaptophysin immunostaining, and glial activation, all of which were pathologic features of human AD. PDDC treatment reduced these changes. The plasma of PDDC-treated PS19 mice had reduced levels of neuronal- and microglial-derived EVs, the former carrying lower pTau levels, compared to untreated mice. In the tau propagation model, PDDC normalized the tau-induced increase in brain ceramides and significantly reduced the amount of tau propagation to the contralateral side. PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity, leading to the slowing of tau spread in AD mice.

更新日期：2023-12-04

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