Presenilin-Dependent Transcriptional Control of the Aβ-Degrading Enzyme Neprilysin by Intracellular Domains of βAPP and APLP

Pardossi‐Piquard, Raphaëlle; Petit, Agnès; Kawarai, Toshitaka; Sunyach, Claire; Costa, Cristine Alves da; Vincent, Bruno; Ring, Sabine; D’Adamio, Luciano; Shen, Jie; Müller, Ulrike; George-Hyslop, Peter St; Checler, Frédéric

doi:10.1016/j.neuron.2005.04.008

Cited by 324 publications

(304 citation statements)

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“…10 Neprilysin gene transcription is reported to be upregulated by APLP-ICDs as well as the ICDs of APP and APLP1. 31 In the present study, based on the previous report that the Fe65 PTB1 domain interacts with the CP2 transcription factor, 19 we reasoned that APLP2-ICDs might interact with the CP2 transcription factor in the nucleus. Therefore, we investigated the interaction of APLP2-ICDs with CP2.…”

Section: Discussionmentioning

confidence: 58%

Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3β expression

et al. 2006

Cell Death Differ

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Amyloid precursor protein (APP) is a member of a gene family that includes two APP-like proteins, APLP1 and 2. Recently, it has been reported that APLP1 and 2 undergo presenilin-dependent c-secretase cleavage, as does APP, resulting in the release of an B6 kDa intracellular C-terminal domain (ICD), which can translocate into the nucleus. In this study, we demonstrate that the APLP2-ICDs interact with CP2/LSF/LBP1 (CP2) transcription factor in the nucleus and induce the expression of glycogen synthase kinase 3b (GSK-3b), which has broad-ranged substrates such as s-and b-catenin. The significance of this finding is substantiated by the in vivo evidence of the increase in the immunoreactivities for the nuclear C-terminal fragments of APLP2, and for GSK-3b in the AD patients' brain. Taken together, these results suggest that APLP2-ICDs contribute to the AD pathogenesis, by inducing GSK-3b expression through the interaction with CP2 transcription factor in the nucleus. The pathology of Alzheimer's disease (AD) is characterized by the deposition of neuritic plaques, of which the principal components are 40 and 42 amino-acid amyloid beta peptides (Ab) derived from amyloid precursor protein (APP). 1 APP belongs to a family of conserved type I transmembrane proteins including Apl-1 in Caenorhabditis elegans, 2 Appl in Drosophila, 3 and APP, 4 APP-like protein 1 (APLP1) 5 and APLP2 6,7 in mammals.APLP1 and 2 display substantial amino-acid and domain homologies with APP. Although they do not have an Ab domain, their intracellular C-terminal domains (ICDs) are highly similar to that of APP. 8 APLP1 is known to be implicated in synaptogenesis, 9,10 and recombinant APLP2 possesses an ability to promote neurite outgrowth. 11 However, their physiological roles in neurons are still not fully understood. In the brains of AD patients, APLP2 immunoreactivity has been detected in a subset of neuritic plaques, 12 suggesting that APLP2 might be involved in the pathogenesis of AD.APLP2 matures through the same secretory/cleavage pathway as APP 7 and previously, APLP1 and 2 were reported to be processed by g-secretase in a presenilin 1-dependent manner. 8,10 The APLP family can be also cleaved by esecretase to generate the ICD composed of the last 50 amino acids of APLPs C-terminus (C50). 13,14 Moreover, the ICDs of APLP1 and APLP2 produced by g-secretase enhanced Fe65-dependent gene transcriptional activation, as have been reported for the APP intracellular domain (AICD). 10 Fe65, which is known to be ones of the adaptor proteins for APP, contains three protein-protein interaction domains, a WW and two phosphotyrosine binding (PTB) domains. The PTB2 domain, which is located in the C-terminal half of the molecule, is responsible for the interaction between Fe65 and the cytosolic tail of APP through the YENPTY domain of APP. 15 Here, we demonstrate that the ICDs of APLP2 (APLP2-ICDs: C57, C50) interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase 3b (GSK-3b) expression, whereas their point mutants with...

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Section: Discussionmentioning

confidence: 58%

Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3β expression

et al. 2006

Cell Death Differ

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“…Along with a mutation within amyloid protein, several important genes have been identified in brains with AD. Presenilin (PSEN) interacts with gamma-secretase, and makes an unusual protease that processes AD-causing Aβ peptide (19,25). Glycogen synthase kinase 3β regulates tau phosphorylation, and overexpressing GSK3β causes AD-like tau protein hyperphosphorylation.…”

Section: Genes Related To Alzheimer's Disease Pathogenesismentioning

confidence: 99%

“…mRNA ratio represented fold difference of each mRNA transcript number of APP-swe cells compared with wt cells. (18)(19)(20)(21). APP also controls aquaporin 1 gene expression by epigenetic control mechanism (22).…”

Section: Introductionmentioning

confidence: 99%

Swedish mutation within amyloid precursor protein modulates global gene expression towards the pathogenesis of Alzheimer's disease

Shin¹,

Yu²,

Yu³

et al. 2010

BMB Reports

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The Swedish mutation (K595N/M596L) of amyloid precursor protein (APP-swe) has been known to increase abnormal cleavage of cellular APP by Beta-secretase (BACE), which causes tau protein hyperphosphorylation and early-onset Alzheimer's disease (AD). Here, we analyzed the effect of APP-swe in global gene expression using deep transcriptome sequencing technique. We found 283 genes were down-regulated and 348 genes were up-regulated in APP-swe expressing H4-swe cells compared to H4 wild-type cells from a total of approximately 74 million reads of 38 base pairs from each transcriptome. Two independent mechanisms such as kinase and phosphatase signaling cascades leading hyperphosphorylation of tau protein were regulated by the expression of APP-swe. Expressions of catalytic subunit as well as several regulatory subunits of protein phosphatases 2A were decreased. In contrast, expressions of tau-phosphorylating glycogen synthase kinase 3β (GSK-3β), cyclin dependent kinase 5 (CDK5), and cAMP-dependent protein kinase A (PKA) catalytic subunit were increased. Moreover, the expression of AD-related Aquaporin 1 and presenilin 2 expression was regulated by APP-swe. Taken

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“…In fact, Fe65 or Fe65-AICD complex interact with nuclear proteins such as Tip60, SET, CP2/LSF (13-15) and experimental evidence indicated that they could be involved in transcription activation (16)(17)(18)(19)(20). However, several studies raised the question of the specificity of this regulation; in particular, De Strooper and colleagues (21) demonstrated that ␥-secretase inhibitors, suppression of presenilins or APP/APLP2 do not induce any significant change in the expression levels of several candidate genes, whereas Fe65 appears to have a rather nonspecific effect on transcription.…”

mentioning

confidence: 99%

Fe65 is required for Tip60-directed histone H4 acetylation at DNA strand breaks

Stante

Minopoli

Passaro

et al. 2009

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

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Fe65 is a binding partner of the Alzheimer's ␤-amyloid precursor protein APP. The possible involvement of this protein in the cellular response to DNA damage was suggested by the observation that Fe65 null mice are more sensitive to genotoxic stress than WT counterpart. Fe65 associated with chromatin under basal conditions and its involvement in DNA damage repair requires this association. A known partner of Fe65 is the histone acetyltransferase Tip60. Considering the crucial role of Tip60 in DNA repair, we explored the hypothesis that the phenotype of Fe65 null cells depended on its interaction with Tip60. We demonstrated that Fe65 knockdown impaired recruitment of Tip60-TRRAP complex to DNA double strand breaks and decreased histone H4 acetylation. Accordingly, the efficiency of DNA repair was decreased upon Fe65 suppression. To explore whether APP has a role in this mechanism, we analyzed a Fe65 mutant unable to bind to APP. This mutant failed to rescue the phenotypes of Fe65 null cells; furthermore, APP/APLP2 suppression results in the impairment of recruitment of Tip60-TRRAP complex to DNA double strand breaks, decreased histone H4 acetylation and repair efficiency. On these bases, we propose that Fe65 and its interaction with APP play an important role in the response to DNA damage by assisting the recruitment of Tip60-TRRAP to DNA damage sites.Alzheimer ͉ APP ͉ DNA repair T he ␤-amyloid peptides, main constituents of senile plaques of Alzheimer disease (AD), derive from the proteolytic processing of a type I membrane protein, known as ␤-amyloid precursor protein (APP) (1). APP functions are not completely understood, and this knowledge could contribute, at least in principle, to the understanding of AD. Possible cues to study the functions of APP could emerge from the analysis of proteins interacting with the short APP cytosolic domain. Several reports indicated that this cytodomain interacts, among the others, with the Fe65 protein (2-4). The latter has the characteristics of an adaptor protein, whose distinctive traits are 3 protein-protein interaction domains, 1 WW and 2 PTB (PhosphoTyrosine Binding) domains (4). The PTB domain located in the C-terminal part of the protein (PTB2) interacts with the cytodomain of APP and of the 2 related proteins APLP1 and APLP2. Similarly, Fe65 has also been found associated with APP intracellular domain (AICD) (5), which is generated, together with the ␤-amyloid peptides, upon the cleavage of APP by secretases (1).Experimental evidence from cultured cells suggested 2 possible functions of Fe65, one depending on its presence in the cytosol and another one on its nuclear localization. APP-Fe65 complexes are present in neuronal growth cones (6) and regulate cell motility (7). Considering that Fe65 WW domain interacts with Mena (8) and APP also with mDab1 (9), these findings support the hypothesis that the APP-Fe65 complex is involved in actin-based membrane remodeling, neurite growth and/or synaptic plasticity. The analysis of the phenotypes of APP/APLP1/APLP2 triple KO ...

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Presenilin-Dependent Transcriptional Control of the Aβ-Degrading Enzyme Neprilysin by Intracellular Domains of βAPP and APLP

Cited by 324 publications

References 56 publications

Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3β expression

Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3β expression

Swedish mutation within amyloid precursor protein modulates global gene expression towards the pathogenesis of Alzheimer's disease

Fe65 is required for Tip60-directed histone H4 acetylation at DNA strand breaks

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