In contrast to these connections to pathology, ApoE provides neuroprotection in many paradigms, and ApoE deficiency has proved add to favorites detrimental in several respects. Therefore, inductions of ApoE by the stimuli we tested may represent a compensatory response, meaning that the distinction between ApoE3 and Inhibitors,Modulators,Libraries ApoE4 repre sents loss of a beneficial function. ApoE has anti inflam matory effects, and even its interaction with Ab can attenuate glial activation by the latter. However, ApoE3 is more effective than ApoE4 as an anti inflam matory agent, so this putative compensatory response may be inadequate in ��4 positive individuals and thus allow more extensive propagation of the Cyto kine Cycle. Such an allele specific compensatory response may also extend to direct neuroprotective activity.

We previously reported that ApoE3 induces bAPP expression but ApoE4 does not, confirming the findings of Ezra et al. In this regard, elevations of ApoE by the process of neuroinflammation, or other stressors, would reflect a requisite role for the lipopro tein in enhancing the beneficial roles of bAPP andor other acute phase response proteins. Thus, it would be the inability of ApoE4 Inhibitors,Modulators,Libraries to participate in this Inhibitors,Modulators,Libraries chain of salutary events that makes it detrimental. We have pre viously shown that the increase in ApoE brain levels that occurs with aging continues to occur in AD, with a large fraction being deposited in plaques. This increase in ApoE levels is distinguishable from changes in bAPP, which rises with age but declines Inhibitors,Modulators,Libraries markedly in AD.

This disease associated severance of the coor dinate regulation of ApoE and bAPP further strengthens the correlation of brain health with the coregulation of these two proteins. to wit, with ApoE expression Inhibitors,Modulators,Libraries itself, provided that the ApoE is not ApoE4. Multi lineage kinase pathways may be invoked in the regulation of ApoE expression, and can themselves be invoked by ApoE, suggesting a feedback loop between MLK pathways and ApoE expression in neu rons. Our findings of involvement of multiple MLKs ERK, p38 MAPK, and JNKin expression of ApoE in neurons exposed to IL 1b, Ab, or sAPP, together with previous reports of ERK pathway invocation of ApoE expression and vice versa, are consistent with the exis tence of a complex feedback system that may be impor tant in acute phase responses to neuronal injury as well as potential exacerbation of neurodegenerative events. Our finding that glutamate regulates ApoE expression via ERK and JNK, but not by p38 MAPK pathways may be indicative of a correlation between glutamatergic induction of ApoE and neuronal survival. Excitotoxic effects of glutamate are largely dependent upon activa tion of extrasynaptic NMDA receptors, p38 MAPK, and the inhibition of ERK selleck products signaling.