Hull Jonathon, Patel Vinood, El Hindy Maya, Lee Christopher, Odeleye Esther, Hezwani Mohammed, Love Seth, Kehoe Patrick, Chalmers Katy, Conway Myra
Faculty of Health and Life Sciences, University of the West of England, Bristol, UK.
Faculty of Science and Technology, University of Westminster, London, UK.
J Alzheimers Dis. 2015;45(3):891-905. doi: 10.3233/JAD-142970.
The human branched chain aminotransferases (hBCATm, mitochondrial and hBCATc, cytosolic) are major contributors to brain glutamate production. This excitatory neurotransmitter is thought to contribute to neurotoxicity in neurodegenerative conditions such as Alzheimer's disease (AD) but the expression of hBCAT in this disease has not previously been investigated.
The objective of investigating hBCAT expression is to gain insight into potential metabolic pathways that may be dysregulated in AD brain, which would contribute to glutamate toxicity.
Western blot analysis and immunohistochemistry were used to determine the expression and localization of hBCAT in postmortem frontal and temporal cortex from AD and matched control brains.
Western blot analysis demonstrated a significant regional increase in hBCATc expression in the hippocampus (↑ 36%; p-values of 0.012), with an increase of ↑ 160% reported for hBCATm in the frontal and temporal cortex (p-values = 4.22 × 10⁻⁴ and 2.79 × 10⁻⁵, respectively) in AD relative to matched controls, with evidence of post-translational modifications to hBCATm, more prominent in AD samples. Using immunohistochemistry, a significant increase in immunopositive labelling of hBCATc was observed in the CA1 and CA4 region of the hippocampus (p-values = 0.011 and 0.026, respectively) correlating with western blot analysis. Moreover, the level of hBCATm in the frontal and temporal cortex correlated significantly with disease severity, as indicated by Braak staging (p-values = 5.63 × 10⁻⁶ and 9.29 × 10⁻⁵, respectively).
The expression of the hBCAT proteins is significantly elevated in AD brain. This may modulate glutamate production and toxicity, and thereby play a role in the pathogenesis of the disease.
人类支链氨基酸转氨酶（线粒体中的hBCATm和胞质中的hBCATc）是大脑谷氨酸生成的主要贡献者。这种兴奋性神经递质被认为在诸如阿尔茨海默病（AD）等神经退行性疾病中导致神经毒性，但此前尚未研究过hBCAT在该疾病中的表达情况。
研究hBCAT表达的目的是深入了解AD大脑中可能失调的潜在代谢途径，这可能导致谷氨酸毒性。
采用蛋白质印迹分析和免疫组织化学方法，确定hBCAT在AD患者及匹配对照者死后额叶和颞叶皮质中的表达及定位。
蛋白质印迹分析表明，与匹配对照相比，AD患者海马中hBCATc表达显著区域性增加（↑36%；p值为0.012），额叶和颞叶皮质中hBCATm分别增加↑160%（p值分别为4.22×10⁻⁴和2.79×10⁻⁵），且有证据表明hBCATm存在翻译后修饰，在AD样本中更为明显。通过免疫组织化学观察到，海马CA1和CA4区域hBCATc免疫阳性标记显著增加（p值分别为0.011和0.026），与蛋白质印迹分析结果相关。此外，额叶和颞叶皮质中hBCATm水平与疾病严重程度显著相关，如Braak分期所示（p值分别为5.63×10⁻⁶和9.29×10⁻⁵）。
hBCAT蛋白在AD大脑中的表达显著升高。这可能调节谷氨酸的生成和毒性，从而在该疾病的发病机制中发挥作用。
