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In vitrostudies show that microglial cells kill neurons treated with the synthetic miniprion (sPrP106) or with amyloid-1-42(a neurotoxic peptide found in Alzheimer's disease) by a process requiring the CD14 protein. The killing of treated primary cortical neurons by microglial cells was reduced by the addition of detoxified lipopolysaccharide (LPS), a deacylated form of LPS. Detoxified LPS also increased the survival of prion-infected neuroblastoma cells incubated with microglial cells. The presence of detoxified LPS reduced cytokine production in these co-cultures, and from isolated microglial cells incubated with native LPS, or fibrils of sPrP106 or amyloid-1-42. These results suggest that some compounds that bind to CD14 might reduce microglial cell activation and increase neuronal survival in prion and Alzheimer's diseases.

Activated microglia are closely associated with neuronal damage in Alzheimer's disease. In the present study, neurons exposed to low concentrations of amyloid-1-42, a toxic fragment of the amyloid- protein, were killed by microglia in a process that required cell–cell contact. Pre-treating microglia with polyclonal antibodies to the CD14 protein, or treating neurons exposed to amyloid-1-42with a CD14-IgG chimera, prevented the killing of amyloid-1-42damaged neurons by microglia. Moreover, microglia from CD14 null mice failed to kill amyloid-1-42damaged neurons. Increased neuronal survival was accompanied by a significant reduction in the production of interleukin-6 indicative of reduced microglial activation. These results indicate an important role for CD14 in the recognition and subsequent killing of amyloid- damaged neurons by microglia.

In the prion diseases, neurodegeneration is preceded by the accumulation of the disease-associated isoform of the prion protein (PrPd). In the present study, neurones treated with three different phospholipase A2inhibitors were resistant to the toxic effects of PrP peptides or a synthetic miniprion (sPrP106). Phospholipase A2inhibitors also protected neurones against a toxic peptide found in Alzheimer's disease (amyloid-1-42). Further studies showed that neurones pre-treated with platelet activating factor (PAF) antagonists were equally resistant to PrP peptides or amyloid-1-42. Moreover, both phospholipase A2inhibitors and PAF antagonists reduced the activation of caspase-3, a marker of apoptosis, and the production of prostaglandin E2that is closely associated with neuronal death in prion or Alzheimer's diseases.

Epidemiological studies have shown that the risk of developing Alzheimer's disease is reduced by the chronic use of classical non-steroidal anti-inflammatory drugs (NSAIDs), drugs that inhibit the cyclo-oxygenase (COX) enzymes that convert arachidonic acid to prostaglandins. In the present study, human SH-SY5Y neuroblastoma cells or murine primary cortical neurones treated with NSAIDs were protected against the otherwise toxic effects of amyloid-1-42. COX-1 selective inhibitors provided greater protection than did COX-2 selective inhibitors or lipoxygenase inhibitors, suggesting that activation of COX-1 is required for amyl oid-1-42-induced neurotoxicity. Although the production of neuronal prostaglandin E2in response to amyloid-1-42was reduced by the presence of COX-1 inhibitors, no neurotoxic effects of prostaglandin E2, or any other prostaglandin, were observed.