Presenilins: Multifunctional Proteins Involved in Alzheimer's Disease Pathology

Presenilins 1 and 2 are two homologous proteins that, when mutated, account for most early onset Alzheimer's disease. Several lines of evidence suggest that, among various functions, presenilins could modulate cell apoptotic responses. Here we establish that the overexpression of presenilin 2 (PS2) and its mutated form Asn-141-Ile-PS2 alters the viability of human embryonic kidney (HEK)293 cells as established by combined trypan blue exclusion, sodium 3′-[1-(phenylamino-carbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid hydrate assay, and propidium iodide incorporation FACS analyses. The two parent proteins increase the acetyl-DEVD-al-sensitive caspase-3-like activity in both HEK293 cells and Telencephalon specific murine neurons, modulate Bax and bcl-2 expressions, and enhance cytochrome C translocation into the cytosol. We show that overexpression of both wild-type and mutated PS2 increases p53-like immunoreactivity and transcriptional activity. We also establish that wild-type- and mutated PS2-induced caspase activation is reduced by p53 antisense approach and by pifithrin-α, a chemical inhibitor of p53. Furthermore, mouse fibroblasts in which the PS2 gene has been knocked out exhibited strongly reduced p53-transcriptional activity. Finally, we establish that the overexpression of both wild-type and mutated PS2 is accompanied by a drastic reduction of endogenous presenilin 1 (PS1) expression. Interestingly, pifithrin-α diminished endogenous PS2 immunoreactivity, whereas the inhibitor increases PS1 expression. Altogether, our data demonstrate that wild-type and familial Alzheimer's disease-linked PS2 trigger apoptosis and down-regulate PS1 expression through p53-dependent mechanisms.

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“…That PS2 and PS1 behave differently and sometimes in an opposite manner has been already suggested (for review, see ref. 4).…”

Section: Discussionmentioning

confidence: 99%

Wild-type and mutated presenilins 2 trigger p53-dependent apoptosis and down-regulate presenilin 1 expression in HEK293 human cells and in murine neurons

Costa

Paitel

Mattson

et al. 2002

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

127

118

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“…Thus, the mutations triggering the genetic forms of Alzheimer all lead to an acceleration of the disease progression that, if not directly because of a modulation of A␤ production, appears at least linked to it (for reviews, see Ref. [42][43][44][45]. This so called "amyloid cascade" hypothesis (46) implies that the secretases that generate A␤ could be considered as major targets of therapeutic strategies aimed at slowing down the onset and progression of the disease.…”

Section: Discussionmentioning

confidence: 99%

BACE1- and BACE2-expressing Human Cells

Andrau

Dumanchin-Njock

Ayral

et al. 2003

Journal of Biological Chemistry

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We have set up stably transfected HEK293 cells overexpressing the ␤-secretases BACE1 and BACE2 either alone or in combination with wild-type ␤-amyloid precursor protein (␤APP). The characterization of the ␤APP-derived catabolites indicates that cells expressing BACEs produce less genuine A␤1-40/42 but higher amounts of secreted sAPP␤ and N-terminal-truncated A␤ species. This was accompanied by a concomitant modulation of the C-terminal counterpart products C89 and C79 for BACE1 and BACE2, respectively. These cells were used to set up a novel BACE assay based on two quenched fluorimetric substrates mimicking the wild-type (JMV2235) and Swedish-mutated (JMV2236) ␤APP sequences targeted by BACE activities. We show that BACEs activities are enhanced by the Swedish mutation and maximal at pH 4.5. The specificity of this double assay for genuine ␤-secretase activity was demonstrated by means of cathepsin D, a "false positive" BACE candidate. Thus, cathepsin D was unable to cleave preferentially the JMV2236-mutated substrate. The selectivity of the assay was also emphasized by the lack of JMV cleavage triggered by other "secretases" candidates such as ADAM10 (A disintegrin and metalloprotease 10), tumor necrosis ␣-converting enzyme, and presenilins 1 and 2. Finally, the assay was used to screen for putative in vitro BACE inhibitors. We identified a series of statine-derived sequences that dose-dependently inhibited BACE1 and BACE2 activities with IC 50 in the micromolar range, some of which displaying selectivity for either BACE1 or BACE2.

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“…␤APP and APLPs are involved in the regulation of PrP c transcription PSs are pleiotropic proteins (Checler, 1999) that are thought to harbor an aspartyl protease activity referred to as ␥-secretase (Wolfe et al, 1999). To assess whether the PS-dependent control of PrP c expression could be linked to ␥-secretase activity, primary cultured neurons were exposed to DAPT, a specific PSdirected inhibitor (Dovey et al, 2001).…”

Section: Presenilins Modulate Cellular Prion Protein At a Transcriptimentioning

confidence: 99%

p53-Dependent Transcriptional Control of Cellular Prion by Presenilins

Vincent¹,

Sunyach²,

Orzechowski³

et al. 2009

J. Neurosci.

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The presenilin-dependent ␥-secretase processing of the ␤-amyloid precursor protein (␤APP) conditions the length of the amyloid ␤ peptides (A␤) that accumulate in the senile plaques of Alzheimer's disease-affected brains. This, together with an additional presenilinmediated -secretase cleavage, generates intracellular ␤APP-derived fragments named amyloid intracellular domains (AICDs) that regulate the transcription of several genes. We establish that presenilins control the transcription of cellular prion protein (PrP c ) by a ␥-secretase inhibitor-sensitive and AICD-mediated process. We demonstrate that AICD-dependent control of PrP c involves the tumor suppressor p53. Thus, p53-deficiency abolishes the AICD-mediated control of PrP c transcription. Furthermore, we show that p53 directly binds to the PrP c promoter and increases its transactivation. Overall, our study unravels a transcriptional regulation of PrP c by the oncogene p53 that is directly driven by presenilin-dependent formation of AICD. Furthermore, it adds support to previous reports linking secretase activities involved in ␤APP metabolism to the physiology of PrP c .

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Presenilins: Multifunctional Proteins Involved in Alzheimer's Disease Pathology

Abstract: SummaryEarly

Cited by 41 publications

References 44 publications

Wild-type and mutated presenilins 2 trigger p53-dependent apoptosis and down-regulate presenilin 1 expression in HEK293 human cells and in murine neurons

Wild-type and mutated presenilins 2 trigger p53-dependent apoptosis and down-regulate presenilin 1 expression in HEK293 human cells and in murine neurons

BACE1- and BACE2-expressing Human Cells

p53-Dependent Transcriptional Control of Cellular Prion by Presenilins

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