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Uptake mechanisms of novel cell-penetrating peptides derived from the Alzheimer’s disease associated gamma-secretase complex
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0001-6107-0844
2006 (English)In: International journal of peptide research and therapeutics, ISSN 1573-3149, Vol. 12, no 2, 105-114 p.Article in journal (Refereed) Published
Abstract [en]

Basic peptides with vector abilities, so called cell-penetrating peptides (CPPs), have been reported to enter cells, carrying cargoes ranging from oligonucleotides and proteins to nanoparticles. In this study we present novel CPPs derived from the gamma-secretase complex, which is involved in the amyloidogenic processing of the amyloid precursor protein (APP) and one of the major research targets for Alzheimer’s disease therapeutics today. In order to examine the uptake efficiency and internalization mechanism of these novel CPPs, side-by-side comparison with the well characterized CPPs penetratin and tat were made. For assessment of the CPP uptake mechanism, endocytosis inhibitors, endosomal markers and cells deficient in the expression of glycosaminoglycans were used. Also, in order to determine the vector ability of the peptides, protein delivery was quantified.

We demonstrate the uptake of the gamma-secretase derived CPPs, in accordance to penetratin and tat, to be largely dependent on temperature and initial binding to cell-surface glycosaminoglycans. After this initial step, there is a discrepancy in the mechanism of uptake, where all peptides, except one, is taken up by a PI 3-kinase dependent fluid phase endocytosis, which could be inhibited by wortmannin. Also, by using endosomal markers and protein delivery efficacy, we conclude that the pathway of internalization for different CPPs could determine the possible cargo size for which they can be used as a vector. The, in this study demonstrated, cell-penetrating properties of the gamma-secretase constituents could prove to be of importance for the gamma-secretase function, which is a matter of further investigation.

Place, publisher, year, edition, pages
2006. Vol. 12, no 2, 105-114 p.
Keyword [en]
Cell-penetrating peptide, CPP, internalization, endocytosis, Alzheimer’s disease, gammasecretase
National Category
Biological Sciences Chemical Sciences
URN: urn:nbn:se:su:diva-23005DOI: 10.1007/s10989-005-9007-yOAI: diva2:189889
Available from: 2006-10-31 Created: 2006-10-31 Last updated: 2015-04-21Bibliographically approved
In thesis
1. Naturally derived cell-penetrating peptides and applications in gene regulation: A study on internalization mechanisms and endosomal escape
Open this publication in new window or tab >>Naturally derived cell-penetrating peptides and applications in gene regulation: A study on internalization mechanisms and endosomal escape
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cell-penetrating peptides are a class of peptides which have achieved a lot of recognition due to their vector abilities. Since their discovery over a decade ago, there has been an uncertainty concerning the mechanism by which they are internalized into the cells. Early studies claimed the uptake to be receptor- and energy independent, whereas more recent studies have shifted the general view to a more endocytotic belief, without prior binding to a receptor. As an increasing amount of reports emerges claiming the uptake to be endocytic, there is still a discrepancy concerning which endocytic mechanism that is responsible for the internalization and how to exploit the endocytic machinery for improved delivery.

The main aim of this thesis was to elucidate the internalization mechanism for a series of cell-penetrating peptides derived from naturally occurring proteins, such as the prion protein which is thought to be the infectious particle in prion disorders. Furthermore, applications in gene regulation and improvement of delivery efficacy by induction of endosomolysis were examined.

The results obtained confirm the uptake of cell-penetrating peptides to be endocytic; however the internalization mechanism appears to be peptide dependent where macropinocytosis is the most widespread endocytic component responsible for the internalization. The results further demonstrate that the biological response can be increased manifold by the induction of endosomolysis, either by using lysosomotropic agents or peptides able to alter their secondary structure upon protonation with concomitant endosomolysis. Altogether the results prove that enhanced delivery using cell-penetrating peptides can be achieved by exploiting the intrinsic endocytic mechanisms involved in the translocation process.

Place, publisher, year, edition, pages
Stockholm: Institutionen för neurokemi, 2006. 83 p.
peptide, oligonucleotide, endocytosis, gene regulation
National Category
urn:nbn:se:su:diva-1328 (URN)
Public defence
2006-12-01, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 13:00 (English)
Available from: 2006-10-31 Created: 2006-10-31 Last updated: 2010-01-11Bibliographically approved

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Langel, Ülo
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