Figure 8

The foam cell hub (simplified). A model for disease development in ATH; similar processes are argued to operate in AD. Only key pathways are depicted. Challenge by infection or proinflammatory agents leads to induction of IFN signaling (*; both IFN-α and IFN-γ. For the specific pathways involved see [257, 309] and references therein), upregulation of macrophage CH25H gene expression, and catalytic conversion of part of the cellular cholesterol pool to 25OHC. Acutely, this molecule exerts anti-pathogen effects via an unknown receptor. On chronic inflammatory exposure, hydroxylated cholesterols accumulate, are removed to insoluble intracellular inclusions by ACAT-mediated esterification (allosterically modulated by oxysterols, a), thereby leading to foam cell formation and overt disease. Oxidation by APP/Aβ may divert or enhance this process. APOE and ABCA1 are shown at the periphery to emphasize their role in export. Other key components from Table 1 (not shown in the figure) include LDLR, a trans-cellular receptor for cholesterol mobilization, and CLU, a protein with diverse functions in complement-mediated cell lysis, apoptosis, and lipid transport. Abbreviations: ABCA1, ATP-binding cassette, sub-family A (ABC1), member 1 (cholesterol efflux protein); ACAT, acyl-CoA cholesterol acyltransferase (also known as SOAT); APOE, apolipoprotein E; APP, amyloid-β (A4) precursor protein (Alzheimer precursor protein); CH25H, cholesterol 25-hydroxylase; CLU, clusterin (apolipoprotein J; complement cytolysis inhibitor); CYP27, cytochrome P450 27A1 (sterol 27-hydroxylase); CYP46, cytochrome P450 46A1 [cholesterol 24(S)-hydroxylase]; CYP7B1, cytochrome P450 7B1 (sterol and steroid 7α hydroxylase); EBI2, Epstein–Barr virus (EBV)-induced G protein-coupled receptor 2, IFN, interferon; LPS, lipopolysaccharide; LDLR, low-density lipoprotein receptor; LXR, liver X receptor; 25OHC, 25-hydroxycholesterol.