The effects of apolipoprotein E and beta amyloid protein on secretion of inflammatory mediators in adult rat microglia

Inflammation has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Microglia are the immune cells in the central nervous system, and when activated they secrete the lipid-derived mediator prostaglandin E2 (PGE2), interleukin-1β (IL-1β), and other inflammatory mediators. The importance of inflammation in AD is underlined by the efficacy of nonsteroidal anti-inflammatory drugs, which block PGE2 production against progression of AD. The epsilon allele of the gene APOE 4, coding for apolipoprotein E epsilon 4 (apoE4), has been shown to correlate with higher risk and earlier age of onset of AD. Excessive accumulation of amyloid deposits and soluble beta amyloid protein (Aβ) occurs in the brain in AD. This study investigated the effects of apoE and Aβ on the regulation of PGE2 and IL-1β secretion in primary microglial culture from adult rat brain cortex. PGE2 and IL-1β were measured by specific enzyme-immunoassay and expression of the PGE2 synthesizing enzyme cyclooxygenase-2 (COX-2) was measured by immunocytochemistry.; The primary finding in this study is that apoE4 alone can stimulate rat microglia in culture to secrete PGE2 and IL-1β in the presence of serum. The increase in PGE2 release was not accompanied by the upregulation of COX-2. Neither Aβ1-40 nor Aβ1-42 alone induced PGE2 and IL-1β secretion from microglia. In studies using a co-stimulator (LPS), the combination of apoE3 and Aβ1-40 inhibited PGE2 and IL-1β secretion stimulated by LPS in serum-free medium. Soluble Aβ1-40 alone did not modulate the LPS-induced secretion of PGE2 in medium with serum, whereas soluble Aβ1-42 attenuated LPS-induced secretion of PGE2 and COX-2 expression. Fibrillar Aβ1-40 or Aβ1-42 themselves did not increase the secretion of PGE2 or modulate LPS induced PGE2 secretion.; In conclusion, apoE4, but not the more common apoE3, activates microglia to secrete the inflammatory mediators PGE2 and IL-1β. This is the first demonstration of a direct inflammatory activity of apoE4. Surprisingly, the Aβ proteins had only minor modulatory effects of microglia in this study.