Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway

Goodger, Zoë V.; Rajendran, Lawrence; Trutzel, Annette; Kohli, Bernhard M.; Nitsch, Roger M.; Konietzko, Uwe

doi:10.1242/jcs.048090

Cited by 112 publications

(121 citation statements)

References 79 publications

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“…NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4330 ARTICLE the exact molecular mechanism of how APP-mediated regulation of miR-574-5p transcription is unclear, we speculate that APP may directly bind to the genomic regions surrounding miR-574-5p through intracellular C-terminal Domain (AICD) of APP, given that AICD can translocate to nucleus upon phosphorylation of APP and mediate some nuclear signalling events [26][27][28] . Next, what is the molecular target of miR-574-5p in regulating the proliferation and differentiation of NPCs?…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein regulates neurogenesis by antagonizing miR-574-5p in the developing cerebral cortex

et al. 2014

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Amyloid precursor protein (APP) is a transmembrane glycoprotein proteolytically processed to release amyloid beta, a pathological hallmark of Alzheimer's disease. APP is expressed throughout the developing and mature brain; however, the primary function of this protein is unknown. We previously demonstrated that APP deficiency enhances neurogenesis, but the mechanisms underlying this process are not known. Here we show that APP regulates the expression of microRNAs in the cortex and in neural progenitors, specifically repressing miR-574-5p. We also show that overexpression of miR-574-5p promotes neurogenesis, but reduces the neural progenitor pool. In contrast, the reduced expression of miR-574-5p inhibits neurogenesis and stimulates proliferation in vitro and in utero. We further demonstrate that the inhibition of miR-574-5p in APP-knockout mice rescues the phenotypes associated with APP deficiency in neurogenesis. Taken together, these results reveal a mechanism in which APP regulates the neurogenesis through miRNA-mediated post-transcriptional regulation.

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Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein regulates neurogenesis by antagonizing miR-574-5p in the developing cerebral cortex

et al. 2014

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“…Some recent evidence would support this viewpoint (20,46), although direct competition between the ␣-and ␤-secretase pathways has more commonly been assumed. Using a cell-based Gal4-driven luciferase reporter gene assay for ␥-secretase-mediated cleavage of APP, Hoey et al (46) showed that treatment of mouse primary cortical neurons with an ␣-secretase inhibitor (TAPI-1) stimulated luciferase activity, whereas a ␤-secretase inhibitor (C3) substantially decreased luciferase activity.…”

Section: Discussionmentioning

confidence: 99%

“…APP 695 is sequestered along with BACE1 and ␥-secretase complexes into lipid raft domains, and processing of the APP occurs following endocytosis where the acidic interior environment favors the catalytic action of the secretases (46), which are aspartic proteinases. The AICD, in combination with Fe65, is delivered to the nucleus by retrograde transport (20), where it can facilitate specific gene transcription, e.g. of the NEP gene (21,24).…”

Section: Discussionmentioning

confidence: 99%

“…By analogy with the Notch intracellular domain (16), AICD has been proposed to act as a transcriptional regulator through its interaction with the adaptor protein Fe65 and its translocation to the nucleus, forming, together with a histone acetyltransferase (Tip60), a transcriptional complex (17) subsequently referred to as an AICD-Fe65-Tip 60 (AFT) complex (18,19). Such "nuclear transcription factories" involving AICD have been directly visualized in nuclei by immunofluorescence microscopy (20). However, the identification and verification of target genes, such as the NEP gene (21), have been highly contentious (22,23).…”

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The Transcriptionally Active Amyloid Precursor Protein (APP) Intracellular Domain Is Preferentially Produced from the 695 Isoform of APP in a β-Secretase-dependent Pathway

Belyaev¹,

Kellett²,

Beckett

et al. 2010

Journal of Biological Chemistry

184

177

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Amyloidogenic processing of the amyloid precursor protein (APP) by ␤-and ␥-secretases generates several biologically active products, including amyloid-␤ (A␤) and the APP intracellular domain (AICD). AICD regulates transcription of several neuronal genes, especially the A␤-degrading enzyme, neprilysin (NEP). APP exists in several alternatively spliced isoforms, APP 695 , APP 751 , and APP 770 . We have examined whether each isoform can contribute to AICD generation and hence up-regulation of NEP expression. Using SH-SY5Y neuronal cells stably expressing each of the APP isoforms, we observed that only APP 695 up-regulated nuclear AICD levels (9-fold) and NEP expression (6-fold). A characteristic feature of Alzheimer disease (AD) 5 is the presence in the brain of extracellular amyloid plaques composed of the amyloid ␤-peptide (principally A␤ 1-40 and A␤ 1-42 ), which is derived from the transmembrane amyloid precursor protein (APP). Hence, for almost two decades, the amyloid cascade hypothesis (1, 2) has driven much AD research with a focus on the prevention of A␤ accumulation or the enhancement of its clearance as primary therapeutic strategies. In the amyloidogenic pathway of APP metabolism, A␤ is formed through the sequential actions of ␤-and ␥-secretases, whereas the non-amyloidogenic ␣-secretase pathway precludes A␤ formation. Enzymic clearance of A␤ is mediated by several enzymes, of which the metallopeptidase neprilysin (NEP) is a key contributor, and up-regulation of A␤-degrading enzymes is a potential therapeutic strategy (3, 4).Three major isoforms of APP are produced due to the alternative splicing of exons 7 and 8, which encode a 56-amino acid Kunitz-type proteinase inhibitor (KPI) domain and a 19-amino acid domain that shares sequence identity with the OX-2 antigen of thymus-derived lymphoid cells, respectively (5). The longest isoform, APP 770 , contains both the KPI and the OX-2 domains, whereas APP 751 contains only the KPI domain. The shortest isoform, APP 695 , lacks both domains. In the brain, APP 695 is expressed at high levels, and the APP 751/770 isoforms are expressed at significantly lower levels, although there are regional differences, and it has been suggested that the balance between the KPI-and non-KPI-containing isoforms may be an important factor influencing A␤ deposition (6). In the AD brain (7-9) and in response to N-methyl-Daspartate (NMDA) receptor stimulation (10, 11), there is an increase in the proportion of KPI-to non-KPI-containing isoforms of APP. This has led to the suggestion that the KPIcontaining isoforms of APP can exert important neuroprotective functions, and thus their up-regulation in the AD brain or in response to excitotoxic insult may be to protect against further neuronal loss (12, 13).A major unmet scientific need in the AD field is still to understand the normal function of APP (14). An added complexity is whether the different APP isoforms have similar or distinct localizations, metabolism, and roles (15). A long standing enigma in APP biology has additi...

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“…Out of 70 ␥-secretase substrates, about 30 generate intracellular domains (ICD) with potential activity in transcriptional regulation (33), including AICD, which is mainly produced via the amyloidogenic pathway (34) and not released from plasma membrane-attached APP. The ␣-secretase-derived C-terminal stub C83 did not produce AICD (8).…”

Section: Possible Sources Of Nuclear Aicd A␤ and Taumentioning

confidence: 99%

Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles

Multhaup

Huber

Buée

et al. 2015

Journal of Biological Chemistry

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Alzheimer disease (AD) 2 is the most common form of dementia and a leading cause of death. Amyloid-␤ (A␤) peptides of varying length (30 -51 amino acid residues) are produced by the sequential, proteolytic processing of the amyloid precursor protein (APP) by ␤-and ␥-secretases (1, 2). In the healthy brain, these protein fragments are normally degraded and eliminated. In the AD brain, the 42-amino acid peptide (A␤42) is prone to form aggregated amyloid oligomers, which are believed to contribute to plaque formation and cognitive decline (3-6).The ␥-secretase also liberates an intracellular fragment called AICD composed of up to 50 residues depending on N-terminal variations (7-9). The first identification of the APP intracellular fragment (AICD) and its detection in brain tissue (8) immediately suggested that it has transcriptional activity, like the Notch intracellular domain (NICD). Whether amyloid A␤ represents a biologically inert bypass product of APP processing or can harbor its own function is a leading question in the AD field. A␤ is potentially toxic depending on its biophysical state (10). Equimolar amounts of the A␤ peptides and the C-terminal fragment AICD are derived from the ␤-C-terminal fragment C99 (11), which represents the APP fragment generated by the initial APP cleavage by ␤-secretase (Fig. 1).A seminal discovery concerning the transcriptional regulatory function of the APP cytoplasmic tail was the observation of its complex formation with Fe65 and the histone acetyltransferase Tip60 and transcriptional activity in reporter gene assays (12). Transactivation of transcription requires ␥-secretase activity and nuclear translocation of Fe65 but not of AICD under these assay conditions (13). However, other studies detected AICD in transcriptional complexes on promoters of target genes using ChIP (see below).In addition, there is evidence that soluble APP fragments (sAPP) of the ectodomain can modulate gene transcription in stimulating downstream signaling through unknown sAPP receptor(s) (14). Accumulation of intracellular A␤ species in neuronal cells before plaque formation leading to concomitant loss of MAP2 expression suggested that A␤ may affect expression or turnover of other proteins (15-17). However, it was not clarified whether this occurs at the transcriptional or translational level.Using a variety of techniques, the recently detected uptake of A␤ peptides into the nuclei of cultured cells (as well as in vivo) revealed that A␤42 possesses unique modulatory activity (18). Direct evidence for the presence of (i) nuclear A␤42 in wildtype animals, (ii) the increased level of nuclear A␤42 in APPoverexpressing animals, and (iii) the detection of nuclear A␤ in quantities comparable with other transcription factors imply a certain biological relevance.The second major hallmark of AD pathology is the presence of neurofibrillary tangles and is associated with intracellular Tau aggregates called neurofibrillary tangles and with modified Tau (19). Although the neuronal Tau (tubulin-associated unit...

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Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway

Abstract: SummaryNuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway

Cited by 112 publications

References 79 publications

Amyloid precursor protein regulates neurogenesis by antagonizing miR-574-5p in the developing cerebral cortex

Amyloid precursor protein regulates neurogenesis by antagonizing miR-574-5p in the developing cerebral cortex

The Transcriptionally Active Amyloid Precursor Protein (APP) Intracellular Domain Is Preferentially Produced from the 695 Isoform of APP in a β-Secretase-dependent Pathway

Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles

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