Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Aged, 80 and over
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Alzheimer Disease / metabolism*
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Peptides / physiology
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Amyloid beta-Protein Precursor / genetics
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Animals
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Apoptosis / genetics
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Apoptosis / physiology
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Brain / cytology
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Brain / metabolism
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Brain / pathology
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Brain Chemistry / genetics
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Cells, Cultured
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Cytosol / chemistry
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DNA / metabolism
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Female
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Fetus
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Genes, p53 / genetics*
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Guinea Pigs
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Heat-Shock Response / genetics
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Humans
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Hydrogen Peroxide / pharmacology
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Intracellular Space / chemistry*
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Intracellular Space / metabolism*
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Intracellular Space / pathology
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Leucine / genetics
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Male
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Membrane Proteins / genetics
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Mice
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Mice, Mutant Strains
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Mice, Transgenic
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Mutation, Missense / genetics
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Nerve Degeneration / metabolism*
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Nerve Degeneration / pathology
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Neuroblastoma / pathology
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Neurons / chemistry
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Neurons / metabolism
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Peptide Fragments / metabolism*
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Peptide Fragments / physiology
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Presenilin-1
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Promoter Regions, Genetic / genetics
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Promoter Regions, Genetic / physiology*
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Protein Binding
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Response Elements / physiology
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / biosynthesis
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Valine / genetics
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Membrane Proteins
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PSEN1 protein, human
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Peptide Fragments
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Presenilin-1
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RNA, Messenger
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Tumor Suppressor Protein p53
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amyloid beta-protein (1-42)
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DNA
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Hydrogen Peroxide
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Leucine
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Valine