John van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge CB2 2PY, UK.
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
Int J Mol Sci. 2022 Jan 19;23(3):1060. doi: 10.3390/ijms23031060.
Iron accumulates in the ageing brain and in brains with neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Down syndrome (DS) dementia. However, the mechanisms of iron deposition and regional selectivity in the brain are ill-understood. The identification of several proteins that are involved in iron homeostasis, transport, and regulation suggests avenues to explore their function in neurodegenerative diseases. To uncover the molecular mechanisms underlying this association, we investigated the distribution and expression of these key iron proteins in brain tissues of patients with AD, DS, PD, and compared them with age-matched controls. Ferritin is an iron storage protein that is deposited in senile plaques in the AD and DS brain, as well as in neuromelanin-containing neurons in the Lewy bodies in PD brain. The transporter of ferrous iron, Divalent metal protein 1 (DMT1), was observed solely in the capillary endothelium and in astrocytes close to the ventricles with unchanged expression in PD. The principal iron transporter, ferroportin, is strikingly reduced in the AD brain compared to age-matched controls. Extensive blood vessel damage in the basal ganglia and deposition of punctate ferritin heavy chain (FTH) and hepcidin were found in the caudate and putamen within striosomes/matrix in both PD and DS brains. We suggest that downregulation of ferroportin could be a key reason for iron mismanagement through disruption of cellular entry and exit pathways of the endothelium. Membrane damage and subsequent impairment of ferroportin and hepcidin causes oxidative stress that contributes to neurodegeneration seen in DS, AD, and in PD subjects. We further propose that a lack of ferritin contributes to neurodegeneration as a consequence of failure to export toxic metals from the cortex in AD/DS and from the substantia nigra and caudate/putamen in PD brain.
铁在衰老的大脑和神经退行性疾病（如阿尔茨海默病（AD）、帕金森病（PD）、亨廷顿病（HD）和唐氏综合征（DS）痴呆）的大脑中积累。然而，铁沉积和大脑区域选择性的机制尚不清楚。一些涉及铁稳态、运输和调节的蛋白质的鉴定表明了探索它们在神经退行性疾病中的功能的途径。为了揭示这种关联的分子机制，我们研究了 AD、DS、PD 患者脑组织中这些关键铁蛋白的分布和表达，并与年龄匹配的对照组进行了比较。铁蛋白是一种铁储存蛋白，在 AD 和 DS 大脑中的老年斑以及 PD 大脑中含神经黑色素的路易体神经元中沉积。亚铁的转运蛋白二价金属蛋白 1（DMT1）仅在毛细血管内皮细胞和靠近脑室的星形胶质细胞中观察到，在 PD 中表达不变。主要铁转运蛋白亚铁蛋白在 AD 大脑中明显减少与年龄匹配的对照组相比。在 PD 和 DS 大脑的纹状体/基质内的尾状核和壳核中，发现基底节广泛的血管损伤和点状铁蛋白重链（FTH）和铁调素沉积。我们认为，铁蛋白的下调可能是通过破坏内皮细胞的细胞内和外排途径导致铁代谢紊乱的关键原因。膜损伤和随后的铁蛋白和铁调素的损伤导致氧化应激，导致 DS、AD 和 PD 患者的神经退行性变。我们进一步提出，铁蛋白的缺乏是由于 AD/DS 大脑皮层和 PD 大脑黑质和尾状核/壳核无法从皮质中排出有毒金属而导致神经退行性变的后果。
