Characterization of human presenilin 1 transgenic rats: increased sensitivity to apoptosis in primary neuronal cultures

Czech, Christian; Lesort, Mathieu; Tremp, Günter; Terro, Faraj; Blanchard, Véronique; Schombert, Brigitte; Carpentier, Nathalie; Dreisler, Sylvie; Bonici, Bruno; Takashima, Akihiko; Moussaoui, Saliha; Hugon, Jacques; Pradier, Laurent

doi:10.1016/s0306-4522(98)00162-6

Cited by 46 publications

(41 citation statements)

References 48 publications

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“…Three different kinds of mutant genes cause early-onset familial AD (FAD): mutant amyloid precursor protein (APP), presenilin (PS)1, and PS2 (1). Accumulated evidence (2)(3)(4)(5)(6)(7)(8)(9)(10) indicates that all these FAD genes can induce death in neuronal cells or augment their vulnerability to other insults. An important clue in the development of AD therapy, therefore, is the molecules that suppress FAD gene-induced death detectable in neuronal cells in culture.…”

mentioning

confidence: 99%

A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ

Hashimoto

Niikura

Tajima

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

557

664

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There is no proof that the HN cDNA represents a gene, that its origin is nuclear, or that the HN peptide is produced in vivo. The information that the long HN cDNA sequence is virtually identical to mitochondrial rRNA should have been put in the Discussion rather than published as supplementary material. The Discussion should have contained the following:The long cDNA [1,567 bp including a poly(A) tail] containing the HN ORF is Ͼ99% identical (1548͞1552) to positions 1679-3230 of mitochondrial DNA (GenBank accession no. AB055387). Because mitochondrial DNA positions 1667-3224 code for mitochondrial 16S rRNA, and mitochondrial 16S rRNA has a short poly(A) tail during transcription (1), the virtual identity of the long HN cDNA to mitochondrial DNA indicates that HN cDNA is mitochondrial 16S rRNA with a poly(A) tail. This makes it unlikely that the peptide encoded by the ORF in HN cDNA is naturally produced. Further, the 75-bp HN ORF is separated from the 5Ј end of the long HN cDNA by a 950-bp region containing at least seven ORFs, each with a stop codon. This makes it even more unlikely that HN peptide is produced from the long HN cDNA. It should also be noted that mitochondria-like nuclear sequences occur commonly as pseudogenes (2). Finally, the HN peptide lacks the characteristic N-terminal signal sequence of secreted peptides, although we suggest that a signal peptide-like function may be encoded in the primary sequence of HN peptide. For all of these reasons, it is unlikely that the HN ORF leads to production of the predicted peptide in vivo.Nonetheless, it remains possible that HN cDNA represents a nuclear transcribed mRNA and that the HN peptide is a natural product. Long regions of the HN cDNA are Ͼ99% identical to certain registered human mRNAs [1545͞1553 at positions 14-1580 of FLJ22981 fis cDNA (AK026634), 925͞929 at positions 1-929 of FLJ22517 fis cDNA, 914͞919 at positions 1348-2266 of FLJ20341 fis cDNA, and 345͞346 at positions 1-346 of PNAS-32 mRNA]. PNAS-32 mRNA is actually expressed to produce NB4 apoptosis-related protein, showing that this mRNA is transcribed from a nuclear gene. In addition, HN cDNA is highly similar to regions of more than 1,000 bp on human chromosomes [positions 245364-244075 of chromosome 11 draft sequence (92%, 1198͞1290), positions 65752-66775 of chromosome X draft sequence (95%, 974͞1025), and positions 687598-688608 of chromosome 5 draft sequence (93%, 954͞1016)]. Also, the HN ORF has a Kozak-like sequence, although it is not canonical.

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mentioning

confidence: 99%

A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ

Hashimoto

Niikura

Tajima

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

557

664

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“…In brief, the coding regions of human wild-type PS1 (PS1 wt) or PS1 containing either one (PS1 M146L) or five distinct FAD mutations (M146L, H163R, A246E, L286V, C410Y) (Sherrington et al, 1995) in one expression construct (PS1 M5) were introduced into a genomic construct with the promotor of the murine 3-hydroxy-3-methyl-glutaryl CoA reductase gene (HMG-CR) that shows a strong and ubiquitous expression pattern in peripheral tissues and in the brain (Gautier et al, 1989;Czech et al, 1998). Western blotting analysis of the different transgenic mouse lines revealed a clear expression of human PS1 in brain and peripheral tissues from transgenic animals.…”

Section: Generation and Characterization Of Transgenic Micementioning

confidence: 99%

“…Western blotting analysis of the different transgenic mouse lines revealed a clear expression of human PS1 in brain and peripheral tissues from transgenic animals. A humanspecific antibody (MAB1563, Chemicon) was used for the detection of full-length PS1 and N-terminal fragments (Czech et al, 1998;Leutner et al, 2000).…”

Section: Generation and Characterization Of Transgenic Micementioning

confidence: 99%

Alzheimer's Disease-like Alterations in Peripheral Cells from Presenilin-1 Transgenic Mice

Eckert

Schindowski

Leutner

et al. 2001

Neurobiology of Disease

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Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. Expression of PS1 mutations in cell culture systems and in primary neurons from transgenic mice increases their vulnerability to cell death. Interestingly, enhanced vulnerability to cell death has also been demonstrated for peripheral lymphocytes from AD patients. We now report that lymphocytes from PS1 mutant transgenic mice show a similar hypersensitivity to cell death as do peripheral cells from AD patients and several cell culture systems expressing PS1 mutations. The cell death-enhancing action of mutant PS1 was associated with increased production of reactive oxygen species and altered calcium regulation, but not with changes of mitochondrial cytochrome c. Our study further emphasizes the pathogenic role of mutant PS1 and may provide the fundamental basis for new efforts to close the gap between studies using neuronal cell lines transfected with mutant PS1, neurons from transgenic animals, and peripheral cells from AD patients.

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“…Also, N141I-PS2 augments death in PC12 cells (Wolozin et al, 1996). FAD mutant PS1 enhances death in PC12 cells (Guo et al, 1996;Weihl et al, 1999) and primary neurons (Czech et al, 1998;Zhang et al, 1998;Guo et al, 1999;Weihl et al, 1999). Rohn et al (2000) and Sudo et al (2000Sudo et al ( , 2001 independently found that treatment of neuronal cells with anti-APP antibody remarkably enhances the neurotoxic function of wild-type (wt) APP, whose overexpression could cause AD type of neurodegeneration in Down's syndrome.…”

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confidence: 99%

Detailed Characterization of Neuroprotection by a Rescue Factor Humanin against Various Alzheimer's Disease-Relevant Insults

et al. 2001

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A novel factor, termed Humanin (HN), antagonizes against neurotoxicity by various types of familial Alzheimer's disease (AD) genes [V642I and K595N/M596L (NL) mutants of amyloid precursor protein (APP), M146L-presenilin (PS) 1, and N141I-PS2] and by A␤1-43 with clear action specificity ineffective on neurotoxicity by polyglutamine repeat Q79 or superoxide dismutase 1 mutants. Here we report that HN can also inhibit neurotoxicity by other AD-relevant insults: other familial AD genes (A617G-APP, L648P-APP, A246E-PS1, L286V-PS1, C410Y-PS1, and H163R-PS1), APP stimulation by anti-APP antibody, and other A␤ peptides (A␤1-42 and A␤25-35). The action specificity was further indicated by the finding that HN could not suppress neurotoxicity by glutamate or prion fragment. Against the AD-relevant insults, essential roles of Cys 8 and Ser 14 were commonly indicated, and the domain from Pro 3 to Pro 19 was responsible for the rescue action of HN, in which seven residues turned out to be essential. We also compared the neuroprotective action of S14G HN (HNG) with that of activity-dependent neurotrophic factor, IGF-I, or basic FGF for the antagonism against various AD-relevant insults (V642I-APP, NL-APP, M146L-PS1, N141I-PS2, and A␤1-43). Although all of these factors could abolish neurotoxicity by A␤1-43, only HNG could abolish cytotoxicities by all of them. HN and HN derivative peptides may provide a new insight into the study of AD pathophysiology and allow new avenues for the development of therapeutic interventions for various forms of AD.

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Characterization of human presenilin 1 transgenic rats: increased sensitivity to apoptosis in primary neuronal cultures

Cited by 46 publications

References 48 publications

A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ

A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ

Alzheimer's Disease-like Alterations in Peripheral Cells from Presenilin-1 Transgenic Mice

Detailed Characterization of Neuroprotection by a Rescue Factor Humanin against Various Alzheimer's Disease-Relevant Insults

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