Abstract
Cholesterol is required for the formation and function of some signalling platforms. In synaptosomes, amyloid-β (Aβ) oligomers, the causative agent in Alzheimer's disease, bind to cellular prion proteins (PrPC) resulting in increased cholesterol concentrations, translocation of cytoplasmic phospholipase A2 (cPLA2, also known as PLA2G4A) to lipid rafts, and activation of cPLA2 The formation of Aβ-PrPC complexes is controlled by the cholesterol ester cycle. In this study, Aβ activated cholesterol ester hydrolases, which released cholesterol from stores of cholesterol esters and stabilised Aβ-PrPC complexes, resulting in activated cPLA2 Conversely, cholesterol esterification reduced cholesterol concentrations causing the dispersal of Aβ-PrPC complexes. In cultured neurons, the cholesterol ester cycle regulated Aβ-induced synapse damage; cholesterol ester hydrolase inhibitors protected neurons, while inhibition of cholesterol esterification significantly increased Aβ-induced synapse damage. An understanding of the molecular mechanisms involved in the dispersal of signalling complexes is important as failure to deactivate signalling pathways can lead to pathology. This study demonstrates that esterification of cholesterol is a key factor in the dispersal of Aβ-induced signalling platforms involved in the activation of cPLA2 and synapse degeneration.
Highlights
The cellular prion protein (PrPC) gained notoriety for its role in the transmissible spongiform encephalopathies after undergoing transformation to the disease-associated isoform (PrPSc)
Immunodepletion with monoclonal antibodies (mAbs) 4G8 reduced the concentrations of Aβ42 (1±0.07 nM compared with 0.03±0.015 nM, n=9, P
The addition of brain extract containing 1 nM Aβ42 to synaptosomes from neurons derived from Prnp knockout(0/0) mice did not significantly alter cholesterol concentrations (0.83±0.07 μM compared with 0.87±0.07 μM, P=0.23, n=9)
Summary
The cellular prion protein (PrPC) gained notoriety for its role in the transmissible spongiform encephalopathies after undergoing transformation to the disease-associated isoform (PrPSc). PrPC is attached to cell membranes via a glycosylphosphatidylinositol (GPI) anchor (Stahl et al, 1987), which targets the protein to specific membrane microdomains called lipid rafts (Taraboulos et al, 1995). Many lipid rafts are enriched with signalling molecules and act as platforms in which GPI anchors interact with signalling proteins (Sharma et al, 2004; Suzuki et al, 2007). PrPC is associated with numerous cell signalling pathways, including those of the tyrosine kinase Fyn (Mouillet-Richard et al, 2000), protein kinase A
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