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Processing of the amyloid precursor protein and its paralogues amyloid precursor-like proteins 1 and 2
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
2007 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Alzheimer’s disease (AD) is a neurodegenerative disorder which is histopathologically characterised by amyloid plaques and neurofibrillary tangles. Amyloid plaques consist of the amyloid β-peptide (Aβ) that can form aggregates in the brain. Aβ is generated from the amyloid precursor protein (APP) through proteolytic cleavage. APP belongs to a conserved protein family that also includes the two paralogues, APP-like proteins 1 and 2 (APLP1 and APLP2). Despite the immense amount of research on APP, motivated by its implication in AD, the function of this protein family has not yet been determined. In this thesis, we have studied the expression and proteolytic processing of the APP protein family. Our results are consistent with previous findings that suggest a role for APP during neuronal development. Treatment of cells with retinoic acid (RA) resulted in increased synthesis. In addition, we observed that RA treatment shifted the processing of APP from the amyloidogenic to the non-amyloidogenic pathway. The proteins in the APP family have been hard to distinguish both with respect to function and proteolytic processing. However, for development of new drugs with APP processing enzymes as targets this is of great importance. Our studies suggest similarities, but also differences in the mechanism regulating the processing of the different paralogues. We found that brain-derived neurotrophic factor (BDNF) had different impact on the members of the APP family. Most interestingly, we also found that the mechanism behind the increased processing in response to IGF-1 was not identical between the homologous proteins. In summary, our results indicate that in terms of regulation APLP1 and APLP2 differ more from each other than from APP. Our studies open up the possibility of finding means to selectively block Aβ production without interfering with the processing and function of the paralogous proteins.

sted, utgiver, år, opplag, sider
Stockholm: Institutionen för neurokemi , 2007. , s. 89
Emneord [en]
APP, APLP1, APLP2, Alzheimer's disease, Amyloid β-peptide, Processing, RA, BDNF, IGF-1, curcumin, PI3-K, MAPK, cdk5
HSV kategori
Forskningsprogram
neurokemi med molekylär neurobiologi
Identifikatorer
URN: urn:nbn:se:su:diva-6763ISBN: 978-91-7155-417-8 (tryckt)OAI: oai:DiVA.org:su-6763DiVA, id: diva2:196998
Disputas
2007-05-11, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2007-04-19 Laget: 2007-04-11 Sist oppdatert: 2018-01-13bibliografisk kontrollert
Delarbeid
1. Accumulation of the amyloid precursor-like protein APLP2 and reduction of APLP1 in retinoic acid-differentiated human neuroblastoma cells upon curcumin-induced neurite retraction
Åpne denne publikasjonen i ny fane eller vindu >>Accumulation of the amyloid precursor-like protein APLP2 and reduction of APLP1 in retinoic acid-differentiated human neuroblastoma cells upon curcumin-induced neurite retraction
Vise andre…
2003 (engelsk)Inngår i: Brain Research. Molecular Brain Research, ISSN 0169-328X, E-ISSN 1872-6941, Vol. 119, nr 1, s. 62-72Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Amyloid precursor protein (APP) belongs to a conserved gene family, also including the amyloid precursor-like proteins, APLP1 and APLP2. The function of these three proteins is not yet fully understood. One of the proposed roles of APP is to promote neurite outgrowth. The aim of this study was to investigate the regulation of the expression levels of APP family members during neurite outgrowth. We observed that retinoic acid (RA)-induced neuronal differentiation of human SH-SY5Y cells resulted in increased expression of APP, APLP1 and APLP2. We also examined the effect of the NFκB, AP-1 and c-Jun N-terminal kinase inhibitor curcumin (diferuloylmethane) on the RA-induced expression levels of these proteins. We found that treatment with curcumin counteracted the RA-induced mRNA expression of all APP family members. In addition, we observed that curcumin treatment resulted in neurite retraction without any effect on cell viability. Surprisingly, curcumin had differential effects on the APLP protein levels in RA-differentiated cells. RA-induced APLP1 protein expression was blocked by curcumin, while the APLP2 protein levels were further increased. APP protein levels were not affected by curcumin treatment. We propose that the sustained levels of APP and the elevated levels of APLP2, in spite of the reduced mRNA expression, are due to altered proteolytic processing of these proteins. Furthermore, our results suggest that APLP1 does not undergo the same type of regulated processing as APP and APLP2.

Emneord
APP, APLP1, APLP2; Curcumin, Retinoic acid, Neurite outgrowth
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-31748 (URN)10.1016/j.molbrainres.2003.08.014 (DOI)000186670700007 ()
Tilgjengelig fra: 2009-12-14 Laget: 2009-11-26 Sist oppdatert: 2018-01-12bibliografisk kontrollert
2. Increased processing of APLP2 and APP with concomitantformation of APP intracellular domains in BDNF and retinoic acid-differentiated human neuroblastoma cells
Åpne denne publikasjonen i ny fane eller vindu >>Increased processing of APLP2 and APP with concomitantformation of APP intracellular domains in BDNF and retinoic acid-differentiated human neuroblastoma cells
2005 (engelsk)Inngår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 95, nr 4, s. 1059-1068Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The amyloid precursor protein (APP) belongs to a conserved gene family, also including the amyloid precursor-like proteins, APLP1 and APLP2. We have previously shown that all members of the APP protein family are up-regulated upon retinoic acid (RA)-induced neuronal differentiation of SH-SY5Y neuroblastoma cells. Here, we demonstrate that RA also affects the processing of APLP2 and APP, as shown by increased shedding of both sAPLP2 and sAPPalpha as well as elevated levels of the APP intracellular domains (AICDs). Brain-derived neurotrophic factor (BDNF) has been reported to induce APP promoter activity and RA induces expression of the tyrosine kinase receptor B (TrkB) in neuroblastoma cells. We show that the increase in shedding of both APLP2 and APP in response to RA is not mediated through the TrkB receptor. However, BDNF concomitant with RA increased the expression of APP even further. In addition, the secretion of sAPLP2 and sAPPalpha, as well as the levels of AICDs increased in response to BDNF. In contrast, the levels of membrane-bound APP C-terminal fragment C99 significantly decreased. Our results suggest that RA and BDNF shifts APP processing towards the alpha-secretase pathway. In addition, we show that RA and BDNF regulate N-linked glycosylation of APLP1.

Emneord
Alzheimer’s disease, amyloid precursor protein, amyloid precursor-like proteins 1 and 2, amyloid precursor protein intracellular domain, processing.
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-31749 (URN)10.1111/j.1471-4159.2005.03440.x (DOI)000232850000014 ()
Tilgjengelig fra: 2009-12-14 Laget: 2009-11-26 Sist oppdatert: 2018-01-12bibliografisk kontrollert
3. The APP processing enzyme ADAM10 is up-regulated by retinoic acid in a PI3-kinase-dependent manner
Åpne denne publikasjonen i ny fane eller vindu >>The APP processing enzyme ADAM10 is up-regulated by retinoic acid in a PI3-kinase-dependent manner
(engelsk)Inngår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468Artikkel i tidsskrift (Fagfellevurdert) Submitted
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-24196 (URN)
Tilgjengelig fra: 2007-04-19 Laget: 2007-04-11 Sist oppdatert: 2017-12-13
4. IGF-1-induced Processing of the Amyloid Precursor Protein Family Is Mediated by Different Signaling Pathways
Åpne denne publikasjonen i ny fane eller vindu >>IGF-1-induced Processing of the Amyloid Precursor Protein Family Is Mediated by Different Signaling Pathways
2007 (engelsk)Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 282, nr 14, s. 10203-10209Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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 beta-peptide (Abeta) 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 Abeta. Insulin and insulin-like growth factor-1 (IGF-1) have been shown to regulate APP processing and the levels of Abeta in the brain. In the present study, we show that IGF-1 increases alpha-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 mitogen-activated 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.

HSV kategori
Identifikatorer
urn:nbn:se:su:diva-21101 (URN)10.1074/jbc.M611183200 (DOI)000245941000010 ()
Tilgjengelig fra: 2007-04-20 Laget: 2007-04-20 Sist oppdatert: 2017-12-13bibliografisk kontrollert

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