Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, New York, Staten Island, USA.
Acta Neuropathol Commun. 2013 Sep 16;1:61. doi: 10.1186/2051-5960-1-61.
Autism is a neurodevelopmental disorder of unknown etiopathogenesis associated with structural and functional abnormalities of neurons and increased formation of reactive oxygen species. Our previous study revealed enhanced accumulation of amino-terminally truncated amyloid-β (Aβ) in brain neurons and glia in children and adults with autism. Verification of the hypothesis that intraneuronal Aβ may cause oxidative stress was the aim of this study.
The relationships between neuronal Aβ and oxidative stress markers-4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA)-were examined in the frontal cortex from individuals aged 7-32 years with idiopathic autism or with chromosome 15q11.2-q13 duplications (dup(15)) with autism, and age-matched controls. Quantification of confocal microscopy images revealed significantly higher levels of neuronal N-truncated Aβ and HNE and MDA in idiopathic autism and dup(15)/autism than in controls. Lipid peroxidation products were detected in all mitochondria and lipofuscin deposits, in numerous autophagic vacuoles and lysosomes, and in less than 5% of synapses. Neuronal Aβ was co-localized with HNE and MDA, and increased Aβ levels correlated with higher levels of HNE and MDA.
The results suggest a self-enhancing pathological process in autism that is initiated by intraneuronal deposition of N-truncated Aβ in childhood. The cascade of events includes altered APP metabolism and abnormal intracellular accumulation of N-terminally truncated Aβ which is a source of reactive oxygen species, which in turn increase the formation of lipid peroxidation products. The latter enhance Aβ deposition and sustain the cascade of changes contributing to metabolic and functional impairments of neurons in autism of an unknown etiology and caused by chromosome 15q11.2-q13 duplication.
自闭症是一种病因不明的神经发育障碍，与神经元的结构和功能异常以及活性氧物质的形成增加有关。我们之前的研究表明，自闭症儿童和成人的大脑神经元和神经胶质中存在截短的淀粉样蛋白-β（Aβ）的积累。本研究旨在验证神经元内 Aβ可能导致氧化应激的假设。
在 7-32 岁患有特发性自闭症或患有染色体 15q11.2-q13 重复（dup(15))并伴有自闭症的个体的额叶皮层中，检查了神经元 Aβ与氧化应激标志物-4-羟基-2-壬烯醛（HNE）和丙二醛（MDA）之间的关系。与对照组相比，特发性自闭症和 dup(15)/自闭症患者的神经元 N 端截断 Aβ和 HNE 以及 MDA 的水平明显更高。共聚焦显微镜图像的定量分析显示，脂质过氧化产物存在于所有线粒体和脂褐素沉积物中，存在于许多自噬小体和溶酶体中，并且少于 5%的突触中。神经元 Aβ与 HNE 和 MDA 共定位，并且 Aβ水平升高与 HNE 和 MDA 水平升高相关。
这些结果表明自闭症中存在一种自我增强的病理过程，该过程由童年时期神经元内 N 端截断 Aβ的沉积引发。该级联反应包括 APP 代谢改变和 N 端截断 Aβ的异常细胞内积累，这是活性氧物质的来源，而活性氧物质又会增加脂质过氧化产物的形成。后者增强了 Aβ的沉积并维持了变化的级联反应，导致了自闭症中神经元的代谢和功能损伤，而自闭症的病因和由染色体 15q11.2-q13 重复引起的损伤尚不清楚。
