Proteoglycan-dependent pathway

The syndecan family of heparin sulfate proteoglycans (HSPGs) plays critical roles in several signal transduction pathways, and syndecan 3 intramembrane proteolysis is presenilin/y-secretase dependent (357). COX2 and COXl potentiate ABP formation through mechanisms that involve y-secretase activity. Sulindac sulfide and other NSAIDs (ibuprofen, indomethacin, R-flurbiprofen) selectively decrease the secretion of ABP independently of COX activity, probably via y-secretase inhibition (358-360). Pepstatin A methylester, sulfonamides, and benzodiazepines can also act as potent, noncompetitive, y-secretase inhibitors (335). These are but a few examples of the potential repercussions and biochemical consequences that the pharmacological manipulation of secretases in AD may bring about. 

Already in 1965, Ryser and Hancock provided evidence that histones and polyamino acids could greatly enhance albumin uptake by cultured tumor cells (6). More recently, several polybasic peptides (so-called protein transduction domains, PTDs or cell-penetrating peptides, CPPs) have been shown to efficiently mediate uptake of nucleic acids, bioactive peptides, phage particles, and liposomes into a wide variety of mammalian cells. The initially proposed ability of CPPs to penetrate plasma membranes via a temperature-independent, non-endocytotic pathway was later shown to be a fixation artifact, and it is currently widely accepted that CPP-mediated macromolecular delivery follows energy-dependent endocytotic pathways that in most cases depend on the expression of cell-surface heparan sulfate proteoglycans (HSPGs) (7). 

Fig. 1 Proposed model for the internalization of PTD-conjugated macromolecules into cells. Interaction of positively charged PTDs with negatively charged proteoglycans and glycosa-minoglycans plays an important role in the internalization. The electrostatic interaction is followed by energy- and temperature-dependent endocytotic pathways. This involves phago-cytotic and pinocytotic pathways clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis...

Chondroitin sulfate proteoglycan-LDL completes are taken up rapidly by macrophages [33, 34] and smooth muscle cells [35]. Such uptake leads to the accumulation of intracellular lipid and the formation of foam cells which are characteristically found in atherosclerotic lesions. Internalization of CSPG-LDL complexes takes place via LDL receptor dependent and independent pathways and is accompanied by decreased degradation of the internalized LDL and increased cholesterol ester synthesis. Thus, proteoglycans not only promote the extracellular retention of lipoproteins but the intracellular retention as well. 

---