Intriguingly, coapplication of glutamate in combination with Ab1 42 reduced the induction to one on par selleck with that of gluta mate alone. Regulation of ApoE expression by IL 1b, Ab, sAPP, and glutamate is via multi lineage kinase pathways Each of the IL 1b induced entities, sAPP and glutamate, as well as Ab, were shown to elevate ApoE expression in both primary neurons and NT2 cells. To begin investigating the mechanisms involved in the induction of such ApoE expression, we focused Inhibitors,Modulators,Libraries on multi lineage kinases previously shown to regu late cytokine induced AD related proteins. Primary neurons and NT2 cells were incubated with inhibitors of three principle MLK pathways, viz, the MEK ERK, MAPK p38, and JNK pathways. Constitutive expression of ApoE in both pri mary neurons and NT2 cells was unaffected by treat ment with these inhibitors.

However, Inhibitors,Modulators,Libraries each of these MLK inhibitors suppressed induction of ApoE by Inhibitors,Modulators,Libraries IL 1b, Ab1 42, and sAPP in both types of culture. Induction of ApoE by glutamate in both NT2 and primary neurons was not inhibited by SB203580, a MAPK p38 inhibitor. Thus, reg ulation of ApoE Inhibitors,Modulators,Libraries expression by MLK pathways appears to be somewhat selective and dependent on the effector of its induction, in the case of glutamate, ERK and JNK activity is involved but not MAPK p38. Discussion The neuroinflammagenic potential of IL 1b is shown here through its induction of synthesis of itself and other proinflammatory cytokines including TNF, IL 1a, IL 1b, as well as the latters maturation enzyme ICE.

The additional impact of IL 1b on neuronal ApoE pro duction shown here suggests that in neurological condi tions where the expression of proinflammatory cytokines is elevated, the expression Inhibitors,Modulators,Libraries of IL 1 driven AD related proteins such as ApoE would be elevated as well. Multiple MLKs ERK, p38 MAPK, and JNK were shown to be involved in elevated expression of ApoE in neu rons exposed to IL 1b, Ab, or sAPP. The increased expression of ApoE induced by glutamate was mediated by ERK and JNK, but not by MAPK p38. Together, these findings have several implications for AD patho genesis, particularly with respect to conditions in which neuroinflammation is prominent, especially those influ enced by APOE genotype. The actions of IL 1 and the other agents tested here sAPP, Ab, and glutamate create the possibility for com plex loops of influence analogous to the vicious circle of neuroinflammatory events we have termed the Cytokine Cycle.

Glutamate can elevate neuronal expression of bAPP and its conversion to sAPP. bAPP is ele vated in dystrophic neurites in and around plaques, its breakdown into both sAPP and Ab can result in induction of IL 1b in microglia. In addition to inducing IL 1b expression and release, sAPP and Ab also stimulate microglia to release biologically relevant levels of glutamate and its cooperative enough excitatory amino acid D serine.