Sabbir Mohammad Golam
Department of Psychology and Neuroscience, College of Psychology, Nova Southeastern University, Fort Lauderdale, FL, United States.
Alzo Biosciences Inc., SanDiego, CA, United States.
Front Cell Dev Biol. 2024 Nov 28;12:1469751. doi: 10.3389/fcell.2024.1469751. eCollection 2024.
Iron is crucial for brain function, but excessive iron is neurotoxic. Abnormally high brain iron accumulation is one of the pathogenic factors in Alzheimer's disease (AD). Therefore, understanding the mechanistic basis of iron dyshomeostasis in AD is vital for disease mitigation. Calcium, another essential bioelement involved in cell signaling, also exhibits dysregulated homeostasis in AD. Calcium ion (Ca) signaling can influence iron homeostasis through multiple effectors. Our previous studies identified Ca/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) as a regulator of transferrin (TF)-bound iron trafficking through the TF receptor (TFRC). Given CAMKK2's high expression in brain cells, it was hypothesized that abnormal CAMKK2-TF/TFRC signaling may underlie excessive iron deposition in AD brains. This study aims to retrospectively investigate CAMKK2, TF, TFRC proteins, and iron content in temporal cortex tissues from AD patients and cognitively normal (CN) individuals, postmortem.
Postmortem temporal cortex tissues from 74 AD patients, 27 Parkinson's disease (PD) patients, and 17 CN individuals were analyzed for CAMKK2, TF, and TFRC protein levels by Western blotting. Additionally, prefrontal/temporal cortex tissues from 30 CN individuals of various ages were examined for age-related effects. Iron content in cortical tissues was measured using a colorimetric assay.
CAMKK2, TF, and TFRC levels were significantly decreased in AD patients' temporal cortices compared to CN individuals, independent of age or postmortem interval-related changes. PD patients' also exhibited similar reductions in CAMKK2/TF/TFRC levels. The increased iron content in AD brains was significantly correlated with reduced TF/TFRC protein levels.
Building on the previous identification of CAMKK2 as a regulator of TF/TFRC trafficking and iron homeostasis, the findings from this study suggest that downregulation of CAMKK2 in AD cortices may disrupt TF/TFRC signaling and contribute to iron overloading and neurodegeneration through iron-induced toxicity. The decreased levels of TF/TFRC and increased iron in AD brains may result from enhanced clearance or post-trafficking degradation of TF/TFRC due to CAMKK2 downregulation. Restoring CAMKK2 levels in the AD brain could offer a novel therapeutic approach to reestablish iron homeostasis. Further studies are needed to explore the pathways linking CAMKK2 and iron dysregulation in AD and other neurodegenerative diseases.
铁对大脑功能至关重要，但过量的铁具有神经毒性。大脑中铁异常高积累是阿尔茨海默病（AD）的致病因素之一。因此，了解AD中铁稳态失调的机制基础对于缓解该疾病至关重要。钙是参与细胞信号传导的另一种必需生物元素，在AD中也表现出稳态失调。钙离子（Ca）信号可通过多种效应器影响铁稳态。我们之前的研究确定钙/钙调蛋白（CaM）依赖性蛋白激酶激酶2（CaMKK2）是通过转铁蛋白受体（TFRC）转运与转铁蛋白（TF）结合的铁的调节因子。鉴于CaMKK2在脑细胞中的高表达，推测CaMKK2-TF/TFR信号异常可能是AD大脑中铁过度沉积的基础。本研究旨在回顾性研究AD患者和认知正常（CN）个体死后颞叶皮质组织中的CaMKK2、TF、TFRC蛋白和铁含量。
通过蛋白质免疫印迹法分析74例AD患者、27例帕金森病（PD）患者和17例CN个体死后的颞叶皮质组织中的CaMKK2、TF和TFRC蛋白水平。此外，对30例不同年龄的CN个体的前额叶/颞叶皮质组织进行年龄相关效应检查。使用比色法测量皮质组织中的铁含量。
与CN个体相比，AD患者颞叶皮质中的CaMKK2、TF和TFRC水平显著降低，与年龄或死后间隔相关变化无关。PD患者的CaMKK2/TF/TFRC水平也有类似降低。AD大脑中铁含量增加与TF/TFRC蛋白水平降低显著相关。
基于之前确定CaMKK2是TF/TFR转运和铁稳态的调节因子，本研究结果表明，AD皮质中CaMKK2的下调可能破坏TF/TFR信号，并通过铁诱导的毒性导致铁过载和神经退行性变。AD大脑中TF/TFRC水平降低和铁增加可能是由于CaMKK2下调导致TF/TFRC的清除增强或转运后降解。恢复AD大脑中的CaMKK2水平可能提供一种重新建立铁稳态的新治疗方法。需要进一步研究探索AD和其他神经退行性疾病中连接CaMKK2和铁失调的途径。
