The amyloid beta -protein (A beta ) ending at 42 plays a pivotal role in Alzheimer's disease (AD). We have reported previously that intracellular A beta 42 is associated with neuronal apoptosis in ...vitro and in vivo. Here, we show that intracellular A beta 42 directly activated the p53 promoter, resulting in p53-dependent apoptosis, and that intracellular A beta 40 had a similar but lesser effect. Moreover, oxidative DNA damage induced nuclear localization of A beta 42 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 A beta 42 and p53 was found in some degenerating-shape neurons in both transgenic mice and human AD cases. Thus, the intracellular A beta 42/p53 pathway may be directly relevant to neuronal loss in AD. Although neurotoxicity of extracellular AP is well known and synaptic/mitochondrial dysfunction by intracellular A beta 42 has recently been suggested, intracellular A beta 42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter; thus demonstrating an alternative pathogenesis in AD.
ABSTRACT
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/mitochondrial dysfunction by intracellular Aβ42 has recently been suggested, intracellular Aβ42 may cause p53‐dependent neuronal apoptosis through activation of the p53 promoter; thus demonstrating an alternative pathogenesis in AD.
The amyloid beta-protein (Abeta) ending at 42 plays a pivotal role in Alzheimer's disease (AD). We have reported previously that intracellular Abeta42 is associated with neuronal apoptosis in vitro ...and in vivo. Here, we show that intracellular Abeta42 directly activated the p53 promoter, resulting in p53-dependent apoptosis, and that intracellular Abeta40 had a similar but lesser effect. Moreover, oxidative DNA damage induced nuclear localization of Abeta42 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 Abeta42 and p53 was found in some degenerating-shape neurons in both transgenic mice and human AD cases. Thus, the intracellular Abeta42/p53 pathway may be directly relevant to neuronal loss in AD. Although neurotoxicity of extracellular Abeta is well known and synaptic/mitochondrial dysfunction by intracellular Abeta42 has recently been suggested, intracellular Abeta42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter; thus demonstrating an alternative pathogenesis in AD.
