The reason of this discrepancy is unknown. Clearly, further work is necessary to resolve this selleck chem Tipifarnib issue in the future. Far less is known about APP gene regulation in astro cytes. TGFb appears to increase APP gene transcription in astrocytes, but few other cytokines have been investi gated. Regulation of astrocytic APP and BACE1 levels may be complex, since additional evidence exists that pro inflammatory cytokines may also control the trans lation of APP and BACE1 mRNA in astrocytes. Importantly, except for our work, none of these studies directly addressed whether Inhibitors,Modulators,Libraries Ab42 oligomers or fibrils could increase astrocytic Inhibitors,Modulators,Libraries APP or BACE1 mRNA levels. BACE1 levels in astrocytes are normally very low compared to neurons.
However, our results have shown that astrocytic BACE1 levels can be strongly induced to 300 600% over control levels when astro cytes are stimulated by cytokine combinations Inhibitors,Modulators,Libraries or Ab42. Moreover, astrocytic APP levels are also increased sev eral fold by cytokine and Ab42 stimulation. Together, these effects result in significantly elevated Inhibitors,Modulators,Libraries b secretase processing of APP and Ab generation in stimulated, as compared to un stimulated, astrocytes. It has not yet been rigorously determined whether stimulated astro cytes produce similar levels of Ab as neurons on a per cell basis, but this seems unlikely. However, because astrocytes greatly outnumber neurons, even a relatively small increase in astrocytic Ab generation may make a significant contribution to the total Ab burden in the AD brain. Our study also suggests that a feed forward mechan ism in AD may operate to elevate and sustain astrocytic amyloidogenic APP processing.
This feed forward mechanism may involve the following steps, 1. Pro inflammatory cytokines including TNF a and IFN g Inhibitors,Modulators,Libraries sti mulate astrocytes to increase levels of BACE1, APP, and secreted Ab, 2. As cerebral Ab levels rise, Ab42 oligo mers and fibrils begin to form, 3. Both oligomeric and fibrillar Ab42 induce and or sustain high levels of astro cytic BACE1, APP, and b secretase processing, 4. Cere bral Ab levels are further elevated, promoting greater cytokine and Ab production, thus creating a vicious cycle. Evidence in favor this hypothesis exists, in that Ab42 is capable of stimulating astrocytes to secrete pro inflammatory cytokines, and conversely cytokine combi nations that include TNF a and IFN g increase astrocy tic Ab synthesis, together forming the elements of a feed forward loop. In addition, it is important to note that the BACE1 cleaved ectodomain of APP, APPsb, is capable of activating microglia. Moreover, kinase inhibitor Paclitaxel Ab itself can cause microglial activation. Thus, microglia are likely to participate in the astrocytic feed forward mechanism as part of a larger cytokine cycle of neuroinflammation.