Single Point Mutation from E22-to-K in Aβ Initiates Early-Onset Alzheimer's Disease by Binding with Catalase

Amyloid-beta (Aβ) is a critical etiological factor for late-onset familial Alzheimer's disease (AD). However, an early-onset AD has been found to be related with an Aβ mutation in glutamic acid 22-to-lysine (Italian type E22K). Why only one single point mutation at E22 residue induces AD remains unclear. Here, we report that a Chinese familial AD pedigree with E22K mutation was associated with higher levels of serum hydrogen peroxide (H(2)O(2)) and lower activity of catalase (a H(2)O(2) degrading enzyme) than controls. Further, we found that E22K binding with catalase caused more severe H(2)O(2) accumulation in the brains of E22K-injected rats than Aβ-injected rats. Unexpectedly, H(2)O(2) bound with the mutation site 22K residue of E22K and elicited more rapid aggregation of E22K than Aβ in vitro. Moreover, H(2)O(2) acted with E22K synergistically to induce higher cellular toxicity than with Aβ. Notably, intrahippocampal infusion of E22K led to more severe plaque deposition, neuron death, and more rapid memory decline than Aβ-injected rats. However, L-cysteine, a H(2)O(2) scavenger, not only prevented self-aggregation of E22K but also reduced H(2)O(2)-promoted E22K assembly in vitro; subsequently, it alleviated Alzheimer-related phenotypes. Hence, E22K binding with catalase promotes the early onset of familial AD, and L-cys may reverse this disease.