Abstract
The cellular prion protein (PrPC) acts as a scaffold protein that organises signalling complexes. In synaptosomes, the aggregation of PrPC by amyloid-β (Aβ) oligomers attracts and activates cytoplasmic phospholipase A2 (cPLA2), leading to synapse degeneration. The signalling platform is dependent on cholesterol released from cholesterol esters by cholesterol ester hydrolases (CEHs). The activation of cPLA2 requires cholesterol released from cholesterol esters by cholesterol ester hydrolases (CEHs), enzymes dependent upon platelet activating factor (PAF) released by activated cPLA2 This demonstrates a positive feedback system in which activated cPLA2 increased cholesterol concentrations, which in turn facilitated cPLA2 activation. PAF was also required for the incorporation of the tyrosine kinase Fyn and cyclooxygenase (COX)-2 into Aβ-PrPC-cPLA2 complexes. As a failure to deactivate signalling complexes can lead to pathology, the mechanisms involved in their dispersal were studied. PAF facilitated the incorporation of acyl-coenzyme A:cholesterol acyltransferase (ACAT)-1 into Aβ-PrPC-cPLA2-COX-2-Fyn complexes. The esterification of cholesterol reduced cholesterol concentrations, causing dispersal of Aβ-PrPC-cPLA2-COX-2-Fyn complexes and the cessation of signalling. This study identifies PAF as a key mediator regulating the cholesterol ester cycle, activation of cPLA2 and COX-2 within synapses, and synapse damage.
Highlights
The cellular prion protein (PrPC) is mainly found in specific membrane micro-domains commonly called lipid rafts (Taraboulos et al, 1995)
Synaptosomes incubated with soluble Alzheimer’s disease (AD) brain extract for 1 h did not have different amounts of cholesterol ester hydrolases (CEHs) compared with that in synaptosomes incubated with control medium (Fig. 1C)
Because Aβ activates cytoplasmic phospholipase A2 (cPLA2) (Palavicini et al, 2017; Zhu et al, 2006), we sought to determine whether activated cPLA2 was involved in the increased synaptic cholesterol concentrations by using two selective cPLA2 inhibitors [arachidonyl trifluoromethyl ketone (AACOCF3) and methyl arachidonyl fluorophosphonate (MAFP)]
Summary
The cellular prion protein (PrPC) is mainly found in specific membrane micro-domains commonly called lipid rafts (Taraboulos et al, 1995). PrPC acts as a scaffold protein that organises signalling complexes (Linden et al, 2012) and is associated with multiple signalling proteins, including the tyrosine kinase Fyn (MouilletRichard et al, 2000) and cytoplasmic phospholipase A2 (cPLA2) (Bate et al, 2010), which are linked to synapse degeneration. PrPC is concentrated at synapses (Herms et al, 1999), and the aggregation of PrPC (Chiesa et al, 2008) or cross-linkage of PrPC with monoclonal antibodies (mAbs) (Solforosi et al, 2004) causes synaptic abnormalities. PrPC has been identified as a receptor for amyloid-β (Aβ) oligomers (Laurén et al, 2009) which are responsible for the synapse degeneration and cognitive decline in patients with Alzheimer’s disease (AD) (Selkoe, 2002; Shankar et al, 2008). The aggregation of PrPC mediated by Aβ oligomers
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