Presenilin-Dependent -Secretase-Mediated Control of p53-Associated Cell Death in Alzheimer's Disease
ABSTRACT Presenilins (PSs) are part of the gamma-secretase complex that produces the amyloid beta-peptide (Abeta) from its precursor [beta-amyloid precursor protein (betaAPP)]. Mutations in PS that cause familial Alzheimer's disease (FAD) increase Abeta production and trigger p53-dependent cell death. We demonstrate that PS deficiency, catalytically inactive PS mutants, gamma-secretase inhibitors, and betaAPP or amyloid precursor protein-like protein 2 (APLP2) depletion all reduce the expression and activity of p53 and lower the transactivation of its promoter and mRNA expression. p53 expression also is diminished in the brains of PS- or betaAPP-deficient mice. The gamma- and epsilon-secretase-derived amyloid intracellular C-terminal domain (AICD) fragments (AICDC59 and AICDC50, respectively) of betaAPP trigger p53-dependent cell death and increase p53 activity and mRNA. Finally, PS1 mutations enhance p53 activity in human embryonic kidney 293 cells and p53 expression in FAD-affected brains. Thus our study shows that AICDs control p53 at a transcriptional level, in vitro and in vivo, and that FAD mutations increase p53 expression and activity in cells and human brains.
- SourceAvailable from: Cristina Lanni
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- "Data from literature indicate that the AFT complex is able to regulate at the transcriptional level different genes such as KAI, neprylisin, EGFR, A␤PP itself , and p53 expression . Moreover AICD-mediated p53 activation can be associated with cell death in Alzheimer's disease (AD)  . "
ABSTRACT: The amyloid-β protein precursor (AβPP) can be processed by either the amyloidogenic or the non-amyloidogenic pathway; both pathways lead to release of the AβPP intracellular C-terminal domain (AICD). AICD involvement in signal transduction within Fe65/Tip60 complex is one of the most discussed mechanisms, and different models have been hypothesized to explain the role of AICD within this complex. The analysis of these models in relation to the degradation processes highlights the discrepancy among AICD localization, function, and degradation, leading to the hypothesis that a signaling mechanism may exist which allows AβPP proteolysis to generate either a transcriptionally active fragment or an inactive one with different involvement of proteasome and IDE (insulin-degrading enzyme). Our work aimed to analyze the functional role of AICD within the Fe65/Tip60 complex considering the AICD degradation processes. Our data suggest a correlation between the role of AICD in gene regulation and its removal operated by proteasome activity. Moreover, treatments with IDE inhibitor underlined the presence of an alternative mechanism involved in AICD removal when the latter is not exerting nuclear activity, thus providing clearer support for the existence of at least two mechanisms as previously suggested.Journal of Alzheimer's disease: JAD 03/2012; 30(2):393-405. DOI:10.3233/JAD-2012-111961 · 3.61 Impact Factor
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- "Knockdown of TMP21 increases c-secretase-mediated Ab production while having no effect on e-secretase-mediate Notch cleavage and amyloid intracellular domain production. Examination of amyloid intracellular domain-regulated elements such as p53 and neprilysin following TMP21 suppression indicates no significant effect on their expression but is accompanied by an elevation of Ab processing (Pardossi-Piquard et al. 2005; Alves Da Costa et al. 2006; Dolcini et al. 2008). TMP21 is expressed in neurons that co-localize with presenilin complex components, and its expression is decreased in Alzheimer disease cases as compared to unaffected controls (Vetrivel et al. 2008). "
ABSTRACT: The presenilin complex is composed of four core proteins (presenilin 1 or presenilin 2, APH1, nicastrin, and PEN2). Several endogenous proteins have been reported to selectively modulate the function of the presenilin complexes; these include transmembrane trafficking protein, 21-KD (TMP21), CD147 antigen (basigin), the γ-secretase-activating protein (gSAP), and the orphan G-protein-coupled receptor 3. Because the structure and assembly of these complexes underlies their activity, this review will discuss current work on the assembly of the complex and on presenilin-interacting proteins that regulate secretase activity.Journal of Neurochemistry 11/2011; 120 Suppl 1:84-8. DOI:10.1111/j.1471-4159.2011.07505.x · 4.24 Impact Factor
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- "o of Ab42 over Ab40 because NEP was shown to degrade the latter peptide more efficiently . This could have pathological consequences since small changes in Ab42 / Ab40 ratio could lead to the exacerbation of cellular toxicity ( Kuperstein et al . 2010 ) . Finally , we recently documented the fact that p53 , that is an AICD transcriptional target ( Alves da Costa et al . 2006 ; Checler et al . 2007 ) , could control Pen - 2 expression and thereby , c - secretase activity ( Dunys et al . 2009 ; Checler et al . 2010"
ABSTRACT: The amyloid-β precursor protein (βAPP) undergoes several cleavages by enzymatic activities called secretases. Numerous studies aimed at studying the biogenesis and catabolic fate of Aβ peptides, the proteinaceous component of the senile plaques that accumulate in Alzheimer's disease-affected brains. Relatively recently, another secretase-mediated β-APP-derived catabolite called APP IntraCellular Domain (AICD) entered the game. Whether AICD corresponded to a biologically inert by-pass product of βAPP processing or whether it could harbor its own function remained questionable. In this study, we review the mechanisms by which AICD is generated and how its production is regulated. Furthermore, we discuss the degradation mechanism underlying its rapid catabolic fate. Finally, we review putative AICD-related functions and more particularly, the numerous studies indicating that AICD could translocate to the nucleus and control at a transcriptional level, the expression of a series of proteins involved in various functions including the control of cell death and Aβ degradation.Journal of Neurochemistry 11/2011; 120 Suppl 1:109-24. DOI:10.1111/j.1471-4159.2011.07475.x · 4.24 Impact Factor