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  • Recent studies suggest that A caused synapse damage as a

    2024-05-15

    Recent studies suggest that Aβ caused synapse damage as a consequence of aberrant cell signalling. As synthetic Aβ42 monomers activate the phosphatidylinositol-3-kinase pathway (Giuffrida et al., 2009) and insulin signalling (Giuffrida et al., 2012) it is possible that Aβ monomers and Aβ oligomers activate different signalling pathways. Here we show that the Aβ oligomers, but not Aβ monomers, activate cPLA2 in synaptosomes, consistent with reports that pharmacological inhibition of cPLA2 protected cultured neurons against Aβ-induced synapse damage (Bate et al., 2010) and ameliorated cognitive decline in a mouse model of AD (Sanchez-Mejia et al., 2008). The activation of cPLA2 by Aβ involves the translocation of cPLA2 to lipid rafts and is sensitive to cholesterol depletion (Bate and Williams, 2011). Here we demonstrate that Aβ oligomers, but not Aβ monomers, increased cholesterol concentrations and activated cPLA2 within synapses. PrPC that is highly expressed at synapses (Brown, 2001, Herms et al., 1999) has been identified as a receptor for Aβ42 (Balducci et al., 2010, Lauren et al., 2009) and the activation of cPLA2 in synapses by Aβ involves PrPC (Bate and Williams, 2011). PrPC is attached to membranes via a glycosylphosphatidylinositol (GPI) anchor (Stahl et al., 1987) and the cross-linkage of GPI-anchored proteins leads to membrane realignment and cell activation (Chen et al., 2006, Suzuki et al., 2007). More specifically, the antibody-mediated cross-linkage of PrPC promotes the formation of lipid rafts and cell signalling in T Ibandronate sodium synthesis (Stuermer et al., 2004). Raft formation is associated with the oligomerization of proteins (Engelman, 2005), specifically GPI-anchored proteins (Eggeling et al., 2009, Suzuki et al., 2012), as the aggregation of membrane components leads to the reorganization of cell membranes (Hammond et al., 2005, Lingwood et al., 2008). We hypothesise that it is the aggregation of PrPC caused by Aβ oligomers that is an essential process leading to synapse damage. Activation of cell signalling pathways is associated with the aggregation of proteins (Suzuki et al., 2007) and here we show that Aβ oligomers, but not monomers, cause PrPC to aggregate, increase synaptic cholesterol concentrations and activate cPLA2. This hypothesis is supported by our observations that the cross-linkage of PrPC by mAb 4F2 mimicked some of the effects of Aβ oligomers upon synaptosomes, including increasing cholesterol concentrations and activating cPLA2; mAb 4F2 also caused synapse degeneration in cultured neurons. In contrast, no changes in synaptic cholesterol concentrations, activation of cPLA2 or synapse damage were observed in synaptosomes or neurons incubated with monovalent Fab fragments derived from mAb 4F2. The reorganization of rafts in the outer leaflet, in response to stimuli, results in the sorting of intracellular signalling molecules on the inner, cytoplasmic leaflet (Eisenberg et al., 2006, Hunter, 2000). Thus, the clustering of individual rafts exposes proteins to new membrane environments and can initiate signalling. Consequently the aggregation of cell surface PrPC can cause the clustering of receptor-associated signalling molecules including cPLA2 within lipid raft platforms. It should be noted that Aβ has been reported to bind to numerous other proteins (Jarosz-Griffiths et al., 2016) meaning that Aβ oligomers have the potential to link PrPC with other proteins. The heterogeneity of complexes formed between Aβ oligomers and numerous different “receptors” may help to explain how Aβ causes the wide variety of cellular responses reported. We report that Aβ monomer preparations protected neurons against the Aβ oligomer-induced synapse damage. These monomers also reduced the Aβ oligomer-induced increase in synaptic cholesterol concentrations and activation of cPLA2 that is closely associated with synapse damage. Aβ monomers did not affect the activation of cPLA2 by PLAP, nor did they affect PLAP-induced synapse damage, indicating that they interfere with a stimulus-specific pathway. Aβ monomers did not cause aggregation of PrPC, consistent with the hypothesis that Aβ contains a single PrPC-binding site and consequently Aβ oligomers, but not Aβ monomers cause the aggregation of PrPC. The presence of Aβ monomers blocks the Aβ oligomer-induced aggregation of PrPC which has been shown to cause cell signalling and synapse degeneration (Bate and Williams, 2012). These results contrast studies that showed that synthetic Aβ42 monomers did not bind to recombinant PrP23–231 (Freir et al., 2011, Nicoll et al., 2013, Um et al., 2012) and suggest that the difference may be the sources of Aβ and PrP proteins used in binding assays (synthetic vs natural). This study also used natural rather than recombinant PrP proteins. The post-translational modifications of PrP include a GPI anchor and N-linked glycosylation, factors which can affect structure and function of some proteins (Butikofer et al., 2001, Elfrink et al., 2008, Kemble et al., 1993). For example, native PrPC contains sialic acid (Rudd et al., 2001, Stahl et al., 1992) a glycan implicated in Aβ binding and structure (Hong et al., 2014, Kakio et al., 2002).