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The amyloid β‐protein (Aβ) ending at 42 plays a pivotal role in Alzheimer's disease (AD). We have reported previously that intracellular Aβ42 is associated with neuronal apoptosis in vitro and in vivo. Here, we show that intracellular Aβ42 directly activated the p53 promoter, resulting in p53‐dependent apoptosis, and that intracellular Aβ40 had a similar but lesser effect. Moreover, oxidative DNA damage induced nuclear localization of Aβ42 with p53 mRNA elevation in guinea‐pig primary neurons. Also, p53 expression was elevated in brain of sporadic AD and transgenic mice carrying mutant familial AD genes. Remarkably, accumulation of both Aβ42 and p53 was found in some degenerating‐shape neurons in both transgenic mice and human AD cases. Thus, the intracellular Aβ42/p53 pathway may be directly relevant to neuronal loss in AD. Although neurotoxicity of extracellular Aβ is well known and synaptic …