While there are few experiments using mixed

While there are few experiments using mixed find more cultures of neurons and glial cells, one study showed that 10 uM Ab42, previously aggregated, induced a decrease of IL 6 levels after two days of incu bation. These contradictory results regarding effects on IL 6 levels of Ab in vitro have also been obtained for brains, peripheral cells, serum and plasma of patients with AD. Inhibitors,Modulators,Libraries TNFa seems to be a critical mediator of the effects of neuroinflammation on early pathology in 3xTgAD mice, and its inhibition in the CNS may slow the appearance of amyloid associated pathology, cogni tive deficits, and potentially the progressive loss of neu rons in AD. These results support the observations made a year before concerning the inhibition of TNFa by thalidomide showing a capacity to prevent amyloid beta induced impairment of recognition memory in mice treated by intracerebral ventricular injection of Ab25 35.

Finally, neutralizing the TNFa pathway by etanercept prevents behavioural changes in an inflammatory rat model obtained by microinjection of IL 1b into the hypothalamus. It has also been shown that ibuprofen suppresses IL 1b induction and ameliorates b amyloid pathology in APPswe mice. Thus, preventing Inhibitors,Modulators,Libraries both TNFa and IL 1b production would seem to be an effi cient strategy to slow damage observed in AD models. To check these literature data suggesting a protective effect of the regulation of inflammation, we studied the apoptotic state of our co cultures. We show that beyond the inhibition of both Ab42 induced TNFa and IL 1b production and release, cells in co cultures display sig nificant reduction of activated pro apoptotic caspase 3 after PKR inhibitor treatment.

Caspase 3 is able to cleave PKR to generate active PKR N terminal and C terminal fragments that play a role in the activation Inhibitors,Modulators,Libraries of intact PKR and contribute to the apoptotic pro cess. Moreover, staining with annexin Inhibitors,Modulators,Libraries V FITC has specified that apoptosis is induced in neurons with axo nal processes drastically altered by Ab42, according to previous studies, and that the PKR inhibitor com pletely prevents this initiation of apoptosis in neurons, displaying a preserved integrity. Although no positive PI staining associated with annexin V FITC was observed, probably due to nuclear lysis, cellular debris are absent in the presence of compound C16, indicating also that this PKR inhibitor prevents Ab42 induced necrosis.

A signal of annexin V FITC was also observed in a few activated microglia in Ab42 treated co cultures and Inhibitors,Modulators,Libraries we can underline that pretreatment with C16 rescued the morphology of microglia from rod microglia to round microglia and astrocytes from spider like to protoplas mic structures. It is well known that caspase 3 is a key factor in TNFa and IL 1b selleck chem induced apoptosis and neu ronal loss in AD.

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