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P1‐113: Accecelerated Aβ plaque formation by low level expression of presenilin‐1 with R278I mutation in knock‐in mouse
Author(s) -
Suemoto Takahiro,
Saito Takashi,
Takano Jiro,
Matsuba Yukio,
Yamazaki Naomi,
Nishimura Masaki,
Iwata Nobuhisa,
Saido Takaomi C.
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.700
Subject(s) - presenilin , missense mutation , microbiology and biotechnology , mutation , biology , reversion , blot , phenotype , mutant , embryonic stem cell , wild type , genetics , alzheimer's disease , pathology , medicine , gene , disease
Background: A ratio of A 42/43 are increased by mutations of presenilin-1 (PS1) associated with lots of familial Alzheimer’s disease (AD). Recently, R278I-PS1 mutation was found to generate a high level of A 43 in vitro using a random mutagenesis screen. Methods: To investigate pathological effects of the mutation, we produced PS1 knock-in (KI) mice with an R278I missense mutation. Results: Unlike PS1 KI mice previously reported, R278I-PS1 homozygous mice were embryonic lethal. The apparent phenotypes (e.g. shortened tail and hemorrhage in the brain) were identical to PS1 knock-out mice. Northern blots and RT-PCR analysis showed normal expression of R278I-PS1 mRNA in the embryonic brain at days 15. By Western blot analysis, remarkable reductions of Nand C-terminal fragments were shown in the brain. Meanwhile, an increase of PS1 holoprotein was ascertained in the mouse embryonic fibroblast (MEF) prepared from R278I-PS1 homozygous mice, which indicated that the processing of PS1 holoprotein to its fragments was impaired by R278I mutation. Additionally, some -secretase substrates, APP CTF, N-cadherin CTF and -synuclein were increased in the embryonic brain. Regardless of low expression of R278I-PS1, A pathologies were accelerated by the mutation. At 6 months of age, A depositions appeared in the cortex of APP23 with R278I-PS1 allele, while no depositions were found in APP23 with wild-type PS1. Increases of A 42 concentration and A 42/40 ratio were detected by ELISA. A ELISA also revealed the increase of A 42/40 ratio in culture medium of R278I-PS1 MEF. Conclusions: It was found that R278I mutation accelerated A pathologies in in R278I-PS1 KI/ APP23 mice, regardless of the low expression of R278I-PS1 protein.