Fig. 12
Schematic summary of hypotheses. a Under physiological conditions astrocytes secrete apoE/HDL particles, which are cleared by several receptors including the low-density lipoprotein receptor (LDLR). Homeostatic microglia surveil brain parenchyma and do not express apoE. b Replication of PrPSc within neurons is the initial culprit of prion pathogenesis and initiates neurodegeneration associated with early astrocyte and microglia activation. Activated microglia remove dying neurons and clear PrPSc. ApoE/HDL secreted by astrocytes promote microglia phagocytosis by activating microglia TREM2 receptor pathway and by opsonization of degenerating neurons. Activated microglia also express lipid poor apoE, which more likely promotes their inflammatory phenotype rather than phagocytosis. c Absence of apoE renders clearance of PrPSc and removal of dying neurons by microglia ineffective. Neuronal remnants promote MGnD activation (i). MGnD microglia secrete a number of inflammatory cytokines including IL1α, TNF-α, and C1qa, which promote A1 neurotoxic astrocytes (ii) and are directly toxic to neurons (iii). Upregulated inflammatory cascade in turn promotes neuronal degeneration and increases the number of dying neurons, which removal is impaired. Thus global Apoe−/− exacerbates prion pathology by propagating the vicious cycle of neuronal death and neuroinflammation. Our data also indicate homeostatic microglia transition to the MGnD even if they do not express apoE