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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
Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
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2003 (English)In: Brain Research. Molecular Brain Research, ISSN 0169-328X, E-ISSN 1872-6941, Vol. 119, no 1, 62-72 p.Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
2003. Vol. 119, no 1, 62-72 p.
Keyword [en]
APP, APLP1, APLP2; Curcumin, Retinoic acid, Neurite outgrowth
National Category
Neurosciences Neurology
Identifiers
URN: urn:nbn:se:su:diva-31748DOI: 10.1016/j.molbrainres.2003.08.014ISI: 000186670700007OAI: oai:DiVA.org:su-31748DiVA: diva2:280998
Available from: 2009-12-14 Created: 2009-11-26 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Processing of the amyloid precursor protein and its paralogues amyloid precursor-like proteins 1 and 2
Open this publication in new window or tab >>Processing of the amyloid precursor protein and its paralogues amyloid precursor-like proteins 1 and 2
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Stockholm: Institutionen för neurokemi, 2007. 89 p.
Keyword
APP, APLP1, APLP2, Alzheimer's disease, Amyloid β-peptide, Processing, RA, BDNF, IGF-1, curcumin, PI3-K, MAPK, cdk5
National Category
Neurosciences
Research subject
Neurochemistry and Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-6763 (URN)978-91-7155-417-8 (ISBN)
Public defence
2007-05-11, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2007-04-19 Created: 2007-04-11 Last updated: 2010-01-12Bibliographically approved
2. Proteolytic processing of the Alzheimer APP protein family during neuronal differentiation
Open this publication in new window or tab >>Proteolytic processing of the Alzheimer APP protein family during neuronal differentiation
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Increased amyloid-β (Aβ) load in the brain, neurite degeneration, neuronal loss, and decreased levels of several neurotrophins are among the characteristics of Alzheimer’s disease (AD). Generation of Aβ occurs when the amyloid precursor protein (APP) is proteolytically processed by β- and γ-secretases in the amyloidogenic pathway. However, Aβ formation is prevented if APP is cleaved by α- and γ- secretases in the non-amyloidogenic pathway. The normal function of APP is still not fully known. It seems clear that the different fragments that are produced during proteolytic processing have different bioactive properties. APP and its metabolites have been implicated in neurite outgrowth, synaptogenesis, cell adhesion, neuroprotection and apoptosis.

The aim of this thesis was to investigate how neurotrophic factors affect the synthesis and processing of APP and its two mammalian paralogues the APP-like protein-1 and-2 (APLP1 and APLP2). We also wanted to determine how the expression levels of α- and β- secretases were affected in response to these factors. In addition, we wanted to analyze if the levels and function of the most well characterized APP adaptor protein, Fe65, was regulated during neuronal differentiation.

Our results show that retinoic acid (RA), insulin-like growth factor-1 (IGF-1), and brain derived neurotrophic factor (BDNF) all regulate expression levels and processing of the APP protein family. Interestingly, the increased processing of the APP family involves different signaling pathways. The PI3-K/Akt pathway is involved in IGF-1-induced APP and APLP1, but not APLP2, processing. In addition, RA-induced expression of the α-secretase, a disintegrin and metalloproteinase (ADAM) 10 is dependent on PI3-K, whereas PKC is involved in RA-induced expression of another α-secretase, ADAM17/TACE. Furthermore, we present evidence that maturation of the adaptor protein Fe65, as well as its docking to APP, increases concomitant with neuronal differentiation.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2009. 82 p.
Keyword
APP, APLP1, APLP2, differentiation, processing, retinoic acid, secretase
National Category
Neurosciences
Research subject
Neurochemistry and Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-31301 (URN)978-91-7155-942-5 (ISBN)
Public defence
2009-12-18, Magnélisalen, Kemiska övningslaboratioriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Manuscript.Available from: 2009-11-26 Created: 2009-11-10 Last updated: 2015-03-09Bibliographically approved

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