Premium
Intracellular Aβ42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer's disease
Author(s) -
Ohyagi Yasumasa,
Asahara Hideaki,
Chui De-Hua,
Tsuruta Yuko,
Sakae Nobutaka,
Miyoshi Katsue,
Yamada Takeshi,
Kikuchi Hitoshi,
Taniwaki Takayuki,
Murai Hiroyuki,
Ikezoe Koji,
Furuya Hirokazu,
Kawarabayashi Takeshi,
Shoji Mikio,
Checler Frederic,
Iwaki Toru,
Makifuchi Takao,
Takeda Kazuya,
Kira Jun-Ichi,
Tabira Takeshi
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2637fje
Subject(s) - intracellular , neurodegeneration , neurotoxicity , microbiology and biotechnology , biology , genetically modified mouse , extracellular , transgene , apoptosis , chemistry , gene , medicine , pathology , genetics , disease , organic chemistry , toxicity
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.