However, it should be noted that AD may take decades to develop and progress, and astro cytes outnumber neurons by over five fold in the brain. Together, these data suggest the possibility that the generation of astrocyte derived Ab, even if low on selleck chemical a per cell basis, could contribute significantly to cerebral Ab levels and exacerbate amyloid pathology over time in AD. A limited Inhibitors,Modulators,Libraries number of studies to date have investigated the effects of pro inflammatory cytokine and Ab stimu lation on BACE1 and APP levels and b secretase proces sing of APP in astrocytes. APP levels have been reported to be elevated by certain pro inflammatory conditions in mouse brain and in human neuroblastoma and non neuronal cells, as well as in human astrocyte cultures, suggesting the potential for amyloidogenic APP proces sing associated with pro inflammatory conditions.

The synergistic effects of TNF a and IFN g on promoting Ab production have been demonstrated for cultured cells including Inhibitors,Modulators,Libraries astrocytes. In addi tion, it has been reported that IFN g alone stimulated BACE1 expression and b secretase Inhibitors,Modulators,Libraries cleavage in human astrocytoma cells and astrocytes derived from Tg2576 transgenic mice that overexpress human APP with the Swedish familial AD mutation, but Inhibitors,Modulators,Libraries its effect on Ab production was not investigated. A subse quent study suggested that the IFN g stimulation acti vated BACE1 gene transcription via the JAK STAT signaling pathway in astrocytes. Inhibitors,Modulators,Libraries Other studies in APP transgenic mice have provided further support for the involvement of TNF a and IFN g in the develop ment of AD related amyloid pathology and memory dysfunction.

One report showed that TNF a and IFN g stimulation increased Ab production in Tg2576 transgenic astrocytes. selleck catalog However, no study to date has explored the effects of TNF a and IFN g on endo genous wild type APP, BACE1 and Ab in astrocytes, which may be more relevant to AD than transgenically overexpressed mutant APP. Conversely, other studies have shown that Ab itself is able to stimulate astrocytes to secrete pro inflammatory molecules in vitro and in vivo. Oligomers of Ab42, the 42 amino acid fibrillogenic form of Ab, dis rupt synaptic function and activate astrocytes. Fibrillar Ab42, which is a primary compo nent of amyloid plaques, also causes astrocyte activation. Together with the cytokine cycle of neuroinflam mation, these results suggest that a feed forward loop may operate during AD whereby cytokines stimulate the production and secretion of Ab in astrocytes, and then astrocytic Ab in turn promotes further cytokine release and astrocytic Ab generation. This is a compelling hypothesis, but direct evidence in support of it has been limited thus far.