Intracellular Abeta42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer's disease.
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.
Ohyagi
Yasumasa
Y
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. ohyagi@neuro.med.kyushu-u.ac.jp
Asahara
Hideaki
H
Chui
De-Hua
DH
Tsuruta
Yuko
Y
Sakae
Nobutaka
N
Miyoshi
Katsue
K
Yamada
Takeshi
T
Kikuchi
Hitoshi
H
Taniwaki
Takayuki
T
Murai
Hiroyuki
H
Ikezoe
Koji
K
Furuya
Hirokazu
H
Kawarabayashi
Takeshi
T
Shoji
Mikio
M
Checler
Frederic
F
Iwaki
Toru
T
Makifuchi
Takao
T
Takeda
Kazuya
K
Kira
Jun-ichi
J
Tabira
Takeshi
T
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry / Q000235:genetics; D002478:Cells, Cultured; D003600:Cytosol / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D005260:Female; D005333:Fetus; D016158:Genes, p53 / Q000235:genetics*; D006168:Guinea Pigs; D018869:Heat-Shock Response / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D042541:Intracellular Space / Q000737:chemistry* / Q000378:metabolism* / Q000473:pathology; D007930:Leucine / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D020125:Mutation, Missense / Q000235:genetics; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism* / Q000502:physiology; D053764:Presenilin-1; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D014633:Valine / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C075222:amyloid beta-protein (1-42); D004247:DNA; D006861:Hydrogen Peroxide; D007930:Leucine; D014633:Valine