Accumulation of the amyloid precursor-like protein APLP2 and reduction of APLP1 in retinoic acid-differentiated human neuroblastoma cells upon curcumin-induced neurite retraction

Adlerz, Linda; Beckman, Marie; Holback, Sofia; Tehranian, Roya; Toro, Veronica Cortés; Iverfeldt, Kerstin

doi:10.1016/j.molbrainres.2003.08.014

Cited by 28 publications

(30 citation statements)

References 63 publications

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“…This raises the possibility that changes in the individual expression levels of the three proteins may influence the shedding of all three family members. In fact, expression levels of APP, APLP1, and APLP2 are regulated differentially upon physiological and pathophysiological stimuli in tissue culture and in vivo, such as during embryonic development, neuronal differentiation, wound repair, and exposure to the curry spice curcumin, which is currently tested as a treatment option for Alzheimer disease (53)(54)(55). Such conditions and stimuli may alter endocytosis and secretion of APP and thus may allow modulating the secretion of the neurotrophic and neuroprotective APPs␣ and of the pathogenic A␤ peptide.…”

Section: Discussionmentioning

confidence: 99%

Amyloid Precursor-like Protein 1 Influences Endocytosis and Proteolytic Processing of the Amyloid Precursor Protein

Neumann

Schöbel

Jäger

et al. 2006

Journal of Biological Chemistry

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Ectodomain shedding of the amyloid precursor protein (APP) is a key regulatory step in the generation of the Alzheimer disease amyloid ␤ peptide (A␤). The molecular mechanisms underlying the control of APP shedding remain little understood but are in part dependent on the low density lipoprotein receptor-related protein (LRP), which is involved in APP endocytosis. Here, we show that the APP homolog APLP1 (amyloid precursor-like protein 1) influences APP shedding. In human embryonic kidney 293 cells expression of APLP1 strongly activated APP shedding by ␣-secretase and slightly reduced ␤-secretase cleavage. As revealed by domain deletion analysis, the increase in APP shedding required the NPTY amino acid motif within the cytoplasmic domain of APLP1. This motif is conserved in APP and is essential for the endocytosis of APP and APLP1. Unrelated membrane proteins containing similar endocytic motifs did not affect APP shedding, showing that the increase in APP shedding was specific to APLP1. In LRP-deficient cells APLP1 no longer induced APP shedding, suggesting that in wild-type cells APLP1 interferes with the LRP-dependent endocytosis of APP and thereby increases APP ␣-cleavage. In fact, an antibody uptake assay revealed that expression of APLP1 reduced the rate of APP endocytosis. In summary, our study provides a novel mechanism for APP shedding, in which APLP1 affects the endocytosis of APP and makes more APP available for ␣-secretase cleavage.The amyloid precursor protein (APP) 2 is one of a large number of membrane proteins that are proteolytically converted to their soluble counterparts. This process is referred to as ectodomain shedding and is an important way of regulating the biological activity of membrane proteins (1, 2). The shedding of APP may occur through two different protease activities termed ␣-and ␤-secretase, which cleave APP within its ectodomain close to its transmembrane domain (for a review, see Ref.3) (see Fig. 1A). APP cleavage by ␣-or ␤-secretase is a key regulatory process in the generation of the amyloid ␤ peptide (A␤). Generation and subsequent deposition of A␤ are assumed to be the first events in the pathogenesis of Alzheimer disease. ␤-Secretase has been identified as the aspartyl protease BACE1 and cleaves APP at the N terminus of the A␤ peptide domain, thus catalyzing the first step in A␤ peptide generation (4). After the initial cleavage of APP by BACE1, the remaining C-terminal APP fragment is cleaved by ␥-secretase within its transmembrane domain at the C terminus of the A␤ domain, leading to the secretion of the A␤ peptide (5). In contrast to ␤-secretase, ␣-secretase cleaves within the A␤ sequence and thereby precludes the generation of the A␤ peptide. ␣-Secretase is a member of the ADAM family of proteases. Candidate ␣-secretases are ADAM10, ADAM17 (TACE), or ADAM9 (6). ␣-Secretase cleavage of APP is assumed to take place at or close to the cell surface, whereas ␤-secretase cleavage takes place after endocytosis of wild-type APP into endosomes. Endocytosis of APP requires t...

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Section: Discussionmentioning

confidence: 99%

Amyloid Precursor-like Protein 1 Influences Endocytosis and Proteolytic Processing of the Amyloid Precursor Protein

Neumann

Schöbel

Jäger

et al. 2006

Journal of Biological Chemistry

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“…Participation of amyloid can not be ruled out, since the expression level of amyloid precursor protein is regulated by retinoid. 23) Other mechanisms might also be possible, and would presumably include a molecular event at the transcriptional level.…”

Section: Discussionmentioning

confidence: 99%

A Synthetic Retinoid Am80 (Tamibarotene) Rescues the Memory Deficit Caused by Scopolamine in a Passive Avoidance Paradigm

Shudo

Kagechika

Yamazaki

et al. 2004

Biological & Pharmaceutical Bulletin

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“…In contrast, a specific MEK inhibitor did not significantly reduce the elevated levels of sAPP␣, excluding the involvement of the MAPK signaling cascade. Previously, we have shown that RA increases the secretion of sAPP␣ concomitant with neurite outgrowth (8,26). PI3-K signaling has been shown to be required for RA-induced differentiation of SH-SY5Y cells (40).…”

Section: Discussionmentioning

confidence: 96%

“…In addition, deficiency in neuronal repair mechanisms after brain injury was observed in Drosophila after deletion of the gene coding for APPL, and both human APP and APPL could induce axonal aborization (7). Previously, we have shown that all members of the APP protein family are up-regulated in parallel with neurite outgrowth in human neuroblastoma SH-SY5Y cells subjected to retinoic acid (RA) (8). Functions during neurogenesis are also supported by in vivo studies in mice showing increased expression of the APP protein family during embryogenesis (9).…”

mentioning

confidence: 99%

IGF-1-induced Processing of the Amyloid Precursor Protein Family Is Mediated by Different Signaling Pathways

Adlerz

Holback

Multhaup

et al. 2007

Journal of Biological Chemistry

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The mammalian amyloid precursor protein (APP) protein family consists of the APP and the amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2). The neurotoxic amyloid ␤-peptide (A␤) originates from APP, which is the only member of this protein family implicated in Alzheimer disease. However, the three homologous proteins have been proposed to be processed in similar ways and to have essential and overlapping functions. Therefore, it is also important to take into account the effects on the processing and function of the APP-like proteins in the development of therapeutic drugs aimed at decreasing the production of A␤. Insulin and insulin-like growth factor-1 (IGF-1) have been shown to regulate APP processing and the levels of A␤ in the brain. In the present study, we show that IGF-1 increases ␣-secretase processing of endogenous APP and also increases ectodomain shedding of APLP1 and APLP2 in human SH-SY5Y neuroblastoma cells. We also investigated the role of different IGF-1-induced signaling pathways, using specific inhibitors for phosphatidylinositol 3-kinase and mitogenactivated protein kinase (MAPK). Our results indicate that phosphatidylinositol 3-kinase is involved in ectodomain shedding of APP and APLP1, but not APLP2, and that MAPK is involved only in the ectodomain shedding of APLP1.

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Accumulation of the amyloid precursor-like protein APLP2 and reduction of APLP1 in retinoic acid-differentiated human neuroblastoma cells upon curcumin-induced neurite retraction

Cited by 28 publications

References 63 publications

Amyloid Precursor-like Protein 1 Influences Endocytosis and Proteolytic Processing of the Amyloid Precursor Protein

Amyloid Precursor-like Protein 1 Influences Endocytosis and Proteolytic Processing of the Amyloid Precursor Protein

A Synthetic Retinoid Am80 (Tamibarotene) Rescues the Memory Deficit Caused by Scopolamine in a Passive Avoidance Paradigm

IGF-1-induced Processing of the Amyloid Precursor Protein Family Is Mediated by Different Signaling Pathways

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