The link between intraneuronal N-truncated amyloid-β peptide and oxidatively modified lipids in idiopathic autism and dup(15q11.2-q13)/autism

Background: 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-beta (A beta)in brain neurons and glia in children and adults with autism. Verification of the hypothesis that intraneuronal A beta may cause oxidative stress was the aim of this study. Results: The relationships between neuronal A beta 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 A beta 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 A beta was co-localized with HNE and MDA, and increased A beta levels correlated with higher levels of HNE and MDA. Conclusions: The results suggest a self-enhancing pathological process in autism that is initiated by intraneuronal deposition of N-truncated A beta in childhood. The cascade of events includes altered APP metabolism and abnormal intracellular accumulation of N-terminally truncated A beta which is a source of reactive oxygen species, which in turn increase the formation of lipid peroxidation products. The latter enhance A beta 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.