Hu Wen, Wu Feng, Zhang Yanchong, Gong Cheng-Xin, Iqbal Khalid, Liu Fei
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, United States.
Key Laboratory of Neuroregeneration of Jiangsu Province and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
Front Aging Neurosci. 2017 Sep 27;9:311. doi: 10.3389/fnagi.2017.00311. eCollection 2017.
Microtubule-associated protein tau is hyperphosphorylated and aggregated in affected neurons in Alzheimer disease (AD) brains. The tau pathology starts from the entorhinal cortex (EC), spreads to the hippocampus and frontal and temporal cortices, and finally to all isocortex areas, but the cerebellum is spared from tau lesions. The molecular basis of differential vulnerability of different brain regions to tau pathology is not understood. In the present study, we analyzed brain regional expressions of tau and tau pathology-related proteins. We found that tau was hyperphosphorylated at multiple sites in the frontal cortex (FC), but not in the cerebellum, from AD brain. The level of tau expression in the cerebellum was about 1/4 of that seen in the frontal and temporal cortices in human brain. In the rat brain, the expression level of tau with three microtubule-binding repeats (3R-tau) was comparable in the hippocampus, EC, FC, parietal-temporal cortex (PTC), occipital-temporal cortex (OTC), striatum, thalamus, olfactory bulb (OB) and cerebellum. However, the expression level of 4R-tau was the highest in the EC and the lowest in the cerebellum. Tau phosphatases, kinases, microtubule-related proteins and other tau pathology-related proteins were also expressed in a region-specific manner in the rat brain. These results suggest that higher levels of tau and tau kinases in the EC and low levels of these proteins in the cerebellum may accounts for the vulnerability and resistance of these representative brain regions to the development of tau pathology, respectively. The present study provides the regional expression profiles of tau and tau pathology-related proteins in the brain, which may help understand the brain regional vulnerability to tau pathology in neurodegenerative tauopathies.
微管相关蛋白tau在阿尔茨海默病（AD）患者大脑中受影响的神经元内发生过度磷酸化并聚集。tau病理改变始于内嗅皮质（EC），扩散至海马体以及额叶和颞叶皮质，最终累及所有同型皮质区域，但小脑未出现tau病变。不同脑区对tau病理改变易感性不同的分子基础尚不清楚。在本研究中，我们分析了tau及与tau病理相关蛋白在脑区的表达情况。我们发现，来自AD患者大脑的额叶皮质（FC）中tau在多个位点发生过度磷酸化，而小脑中则未出现这种情况。人脑中tau在小脑的表达水平约为额叶和颞叶皮质的1/4。在大鼠脑中，具有三个微管结合重复序列（3R-tau）的tau表达水平在海马体、EC、FC、顶颞叶皮质（PTC）、枕颞叶皮质（OTC）、纹状体、丘脑、嗅球（OB）和小脑中相当。然而，4R-tau的表达水平在EC中最高，在小脑中最低。tau磷酸酶、激酶、微管相关蛋白及其他与tau病理相关的蛋白在大鼠脑中也呈区域特异性表达。这些结果表明，EC中较高水平的tau和tau激酶以及小脑中这些蛋白的低水平可能分别解释了这些代表性脑区对tau病理发展的易感性和抗性。本研究提供了脑中tau及与tau病理相关蛋白的区域表达谱，这可能有助于理解神经退行性tau病中脑区对tau病理的易感性。
