Neurodegeneration of Trigeminal Mesencephalic Neurons by the Tooth Loss Triggers the Progression of Alzheimer's Disease in 3×Tg-AD Model Mice.
Neurodegeneration of Trigeminal Mesencephalic Neurons by the Tooth Loss Triggers the Progression of Alzheimer's Disease in 3×Tg-AD Model Mice.
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DOI：
10.3233/jad-200257
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Chang RC
中科院分区：
文献类型：
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作者：
Goto T;Kuramoto E;Dhar A;Wang RP;Seki H;Iwai H;Yamanaka A;Matsumoto SE;Hara H;Michikawa M;Ohyagi Y;Leung WK;Chang RC
三叉神经中脑核(VMES)不仅在解剖上与蓝斑(LC)相邻，而且与LC的功能密切相关。LC可能是阿尔茨海默病(AD)发生的第一个区域，尽管尚不清楚LC神经元丢失是如何发生的。我们研究了在雌性三转基因(3×TG)-AD小鼠中，VME区神经元的死亡是否可以扩散到邻近的LC，淀粉样蛋白-β(Aβ)如何参与LC神经元的丢失，以及这种神经变性如何影响认知功能。取3只TG-AD小鼠的磨牙，饲养1周~4个月。采用免疫组织化学方法和Barnes迷宫进行空间学习记忆能力评估。4个月龄3×TG-AD小鼠VME神经元内可见聚集的细胞毒A-β-42颗粒。拔牙后VME区神经元死亡，细胞毒A CD42释放，β免疫反应阳性小胶质细胞增多。释放的Aβ42损害了LC，进而导致接受LC投射的CA1区和CA3区的海马神经元显著减少。基于空间学习记忆测试，4月龄3×TG-AD小鼠拔牙后，5月龄3×TG-AD小鼠1个月后潜伏期延长，与对照组8月龄3×TG-AD小鼠潜伏期延长相似。对认知缺陷的测量表明，拔牙后较早地转变为痴呆症样行为。这些发现表明，在痴呆前期拔牙可能会引发VME、LC和海马区的神经变性扩散，并加速痴呆的发病。
The mesencephalic trigeminal nucleus (Vmes) is not only anatomically adjacent to the locus coeruleus (LC) but is also tightly associated with the function of the LC. The LC can be the first area in which Alzheimer’s disease (AD) develops, although it is unclear how LC neuronal loss occurs. We investigated whether neuronal death in the Vmes can be spread to adjacent LC in female triple transgenic (3×Tg)-AD mice, how amyloid-β (Aβ) is involved in LC neuronal loss, and how this neurodegeneration affects cognitive function. The molars of 3×Tg-AD mice were extracted, and the mice were reared for one week to 4 months. Immunohistochemical analysis, and spatial learning/memory assessment using the Barnes maze were carried out. In 4-month-old 3×Tg-AD mice, aggregated cytotoxic Aβ42 was found in granules in Vmes neurons. Neuronal death in the Vmes occurred after tooth extraction, resulting in the release of cytotoxic Aβ42 and an increase in CD86 immunoreactive microglia. Released Aβ42 damaged the LC, in turn inducing a significant reduction in hippocampal neurons in the CA1 and CA3 regions receiving projections from the LC. Based on spatial learning/memory assessment, after the tooth extraction in the 4-month-old 3×Tg-AD mice, increased latency was observed in 5-month-old 3×Tg-AD mice 1 month after tooth extraction, which is similar increase of latency observed in control 8-month-old 3×Tg-AD mice. Measures of cognitive deficits suggested an earlier shift to dementia-like behavior after tooth extraction. These findings suggest that tooth extraction in the predementia stage can trigger the spread of neurodegeneration from the Vmes, LC, and hippocampus and accelerate the onset of dementia.