PDF(Pubmed)
Abstract：
The tau protein phosphorylated at Thr181 (p-tau181) in cerebrospinal fluid and blood is a sensitive biomarker for Alzheimer\'s disease (AD). Increased p-tau181 levels correlate well with amyloid-β (Aβ) pathology and precede neurofibrillary tangle formation in the early stage of AD; however, the relationship between p-tau181 and Aβ-mediated pathology is less well understood. We recently reported that p-tau181 represents axonal abnormalities in mice with Aβ pathology (AppNLGF). However, from which neuronal subtype(s) these p-tau181-positive axons originate remains elusive.
The main purpose of this study is to differentiate neuronal subtype(s) and elucidate damage associated with p-tau181-positive axons by immunohistochemical analysis of AppNLGF mice brains.
Colocalization between p-tau181 and (1) unmyelinated axons positive for vesicular acetylcholine transporter or norepinephrine transporter and (2) myelinated axons positive for vesicular glutamate transporter, vesicular GABA transporter, or parvalbumin in the brains of 24-month-old AppNLGF and control mice without Aβ pathology were analyzed. The density of these axons was also compared.
Unmyelinated axons of cholinergic or noradrenergic neurons did not overlap with p-tau181. By contrast, p-tau181 signals colocalized with myelinated axons of parvalbumin-positive GABAergic interneurons but not of glutamatergic neurons. Interestingly, the density of unmyelinated axons was significantly decreased in AppNLGF mice, whereas that of glutamatergic, GABAergic, or p-tau181-positive axons was less affected. Instead, myelin sheaths surrounding p-tau181-positive axons were significantly reduced in AppNLGF mice.
This study demonstrates that p-tau181 signals colocalize with axons of parvalbumin-positive GABAergic interneurons with disrupted myelin sheaths in the brains of a mouse model of Aβ pathology.
The main purpose of this study is to differentiate neuronal subtype(s) and elucidate damage associated with p-tau181-positive axons by immunohistochemical analysis of AppNLGF mice brains.
Colocalization between p-tau181 and (1) unmyelinated axons positive for vesicular acetylcholine transporter or norepinephrine transporter and (2) myelinated axons positive for vesicular glutamate transporter, vesicular GABA transporter, or parvalbumin in the brains of 24-month-old AppNLGF and control mice without Aβ pathology were analyzed. The density of these axons was also compared.
Unmyelinated axons of cholinergic or noradrenergic neurons did not overlap with p-tau181. By contrast, p-tau181 signals colocalized with myelinated axons of parvalbumin-positive GABAergic interneurons but not of glutamatergic neurons. Interestingly, the density of unmyelinated axons was significantly decreased in AppNLGF mice, whereas that of glutamatergic, GABAergic, or p-tau181-positive axons was less affected. Instead, myelin sheaths surrounding p-tau181-positive axons were significantly reduced in AppNLGF mice.
This study demonstrates that p-tau181 signals colocalize with axons of parvalbumin-positive GABAergic interneurons with disrupted myelin sheaths in the brains of a mouse model of Aβ pathology.
摘要：
背景：脑脊液和血液中Thr181磷酸化的tau蛋白（p-tau181）是阿尔茨海默病（AD）的敏感生物标志物。p-tau181水平的升高与淀粉样蛋白-β(Aβ)病理和AD早期神经原纤维缠结形成密切相关;然而,p-tau181与Aβ介导的病理学之间的关系尚不清楚。我们最近报道，p-tau181代表具有Aβ病理（AppNLGF）的小鼠的轴突异常。然而,这些p-tau181阳性轴突的神经元亚型起源仍然难以捉摸。
目的：本研究的主要目的是通过对AppNLGF小鼠大脑的免疫组织化学分析来区分神经元亚型并阐明与p-tau181阳性轴突相关的损伤。
方法：p-tau181与（1）囊泡乙酰胆碱转运体或去甲肾上腺素转运体阳性的无髓鞘轴突和（2）囊泡谷氨酸转运体阳性的有髓鞘轴突之间的定位，囊泡GABA转运蛋白，分析了24个月大的AppNLGF和没有Aβ病理的对照小鼠的大脑中的或小白蛋白。还比较了这些轴突的密度。
结果：胆碱能或去甲肾上腺素能神经元的无髓鞘轴突与p-tau181不重叠。相比之下,p-tau181信号与小白蛋白阳性GABA能中间神经元的有髓轴突共定位，但与谷氨酸能神经元无关。有趣的是,在AppNLGF小鼠中，无髓轴突的密度显著降低，而谷氨酸能，GABA能,或p-tau181阳性轴突受影响较小。相反，在AppNLGF小鼠中,p-tau181阳性轴突周围的髓鞘显著减少.
结论：这项研究表明，p-tau181信号与Aβ病理小鼠模型大脑中的小白蛋白阳性GABA能中间神经元的轴突共定位，髓鞘被破坏。
目的：本研究的主要目的是通过对AppNLGF小鼠大脑的免疫组织化学分析来区分神经元亚型并阐明与p-tau181阳性轴突相关的损伤。
方法：p-tau181与（1）囊泡乙酰胆碱转运体或去甲肾上腺素转运体阳性的无髓鞘轴突和（2）囊泡谷氨酸转运体阳性的有髓鞘轴突之间的定位，囊泡GABA转运蛋白，分析了24个月大的AppNLGF和没有Aβ病理的对照小鼠的大脑中的或小白蛋白。还比较了这些轴突的密度。
结果：胆碱能或去甲肾上腺素能神经元的无髓鞘轴突与p-tau181不重叠。相比之下,p-tau181信号与小白蛋白阳性GABA能中间神经元的有髓轴突共定位，但与谷氨酸能神经元无关。有趣的是,在AppNLGF小鼠中，无髓轴突的密度显著降低，而谷氨酸能，GABA能,或p-tau181阳性轴突受影响较小。相反，在AppNLGF小鼠中,p-tau181阳性轴突周围的髓鞘显著减少.
结论：这项研究表明，p-tau181信号与Aβ病理小鼠模型大脑中的小白蛋白阳性GABA能中间神经元的轴突共定位，髓鞘被破坏。
