In conclusion, the induction PD173955? of neuronal ApoE by either neuroinflammatory or excitotoxic agents or neu rotoxins, acting through MLK pathways suggests that alterations in these signaling pathways, together with other neuropathological entities in AD brain, may have consequences for ApoE expression. Differences in this expression may be critical, considering the role of APOE genotype in AD risk. The response of ApoE to IL 1b we show here in rodent brain suggests that elevation of IL 1 leads to the increases in ApoE that we and others have observed in the AD brain. This may have added significance with regard to the self propagating nature of IL 1 driven cascades, especially when such cascades are instigated in the context of an ��4 allele of APOE.

While induction of ApoE2 or ApoE3 may be anti inflammatory or neuroprotective, and thereby act as a self limiting influence on IL 1 driven cascades, ApoE4 may fail to participate and leave the brain vulnerable to prolonged activation of a maladaptive cycle. Background Prion diseases, also known as transmissible spongiform encephalopathies, are fatal neurodegenerative Inhibitors,Modulators,Libraries disorders, characterized by brain vacuolation, neuronal cell death, and microgliosis. They are caused by the conversion of cellular prion protein into the pathological isoform through conformational changes. PrPSc is protease resistant, and has a higher proportion of B sheet structure in place of the normal helix structure. The accumu lation of abnormal forms of prion protein has been shown to be the main causative agent of these diseases.

The neurotoxic PrP fragment 106126 pos sesses similar physicochemical Inhibitors,Modulators,Libraries and pathogenic properties to PrPSc, in that it forms amyloid fibrils with a high B sheet content, shows partial proteinase K resistance, and is neuro toxic in vitro. Therefore, PrP106 126 is commonly used as a model for the investigation of PrPSc neurotoxicity. A large number of studies have shown that Inhibitors,Modulators,Libraries the accu mulation of aggregated PrPSc leads to activation of micro glia, and these in turn produce chemotatic factors, pro inflammatory cytokines, and neurotoxic factors. Furthermore, studies on brains from prion infected mice have found upregulation of multiple cytokines and chemo kines, including interleukin 1B, tumor necrosis factor, and chemokine ligand 3. IL 1B plays a central role in the regulation Inhibitors,Modulators,Libraries of immune and inflammatory responses.

It is Inhibitors,Modulators,Libraries produced as the in active precursor pro IL 1B in the cytosol, and a variety of stimuli can lead to higher expression of pro IL 1B. The inactive pro IL 1B can be cleaved by protease caspase 1 into the mature, active form, IL 1B. Several studies have shown that synthetic neurotoxic prion frag ments activate mouse microglia and lead to an increase in the production of IL 1B in vitro. however, the mechanism by which PrP106 126 induces selleck compound IL 1B release is yet unknown.