Although their contribution to the clearance of Aβ deposits is thought to be protective, there is also evidence to suggest that microglia and astrocytes contribute to the progression of AD. One obvious explanation is that the physiological functions of astrocytes may be directly HIF-1�� pathway affected by Aβ. For instance, in a elegant study using fluorescence imaging microscopy in live mice

bearing AD-like pathology, intracellular Ca2+ signaling was reported to be abnormally increased in astrocytes, sometimes propagating as intracellular calcium waves.133 These Ca2+ transients were only observed after the mice developed senile plaques and were uncoupled from neuronal activity, suggesting that Aβ interacts Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical directly with the astrocytic network.133 The involvement of glial cells in the pathogenesis of AD is supported by several in vitro studies demonstrating that their interaction with Aβ impairs neuronal viability or worsens the neurotoxic effect of Aβ.134,138 Upon their activation by Aβ, astrocytes and microglia can release a number of inflammatory mediators which may be toxic for surrounding neurons. Examples include proinflammatory

cytokines such as IL-1β and IL-6, and reactive oxygen and nitrogen species (RN/ROS) such as NO and O2 -.132,139-143 Proinflammatory cytokines have been shown to exacerbate the microglial response to Aβ and to enhance Inhibitors,research,lifescience,medical its neurotoxic effects.144-146 Moreover, it appears that proinflammatory cytokines can also increase the expression of the amyloid precursor protein and its processing through amyloidogenic pathways.147-149 Aβ accumulation may therefore establish a vicious circle whereby neuronal stress and glial activation initiates an inflammatory response, which in turn Inhibitors,research,lifescience,medical promotes the synthesis and accumulation of more Aβ, thus perpetuating glial cell activation. This may in part explain why age is the most important risk factor for Inhibitors,research,lifescience,medical developing AD since increased neuroinflammation is associated with normal aging.150 This enhancement

of the basal inflammatory state, together with the gradual accumulation of Aβ which is also seen in the normal aging brain, may provide the trigger next necessary for this vicious circle to set in. Because of their central role in neuroinflammation (see previous section), glial cells may provide a valuable therapeutic target for the treatment of AD. This is supported by studies testing newly identified antiinflammatory molecules which selectively suppress proinflammatory cytokines production in glia, resulting in a significant attenuation of synaptic dysfunction and neurodegeneration and in behavioral improvements in experimental models of AD.151,152 Besides proinflammatory cytokines, RN/ROS produced by activated astrocytes and microglia may contribute to disease progression by inducing oxidative stress, a hallmark of AD.142,153 Astrocytes have been proposed to take part in this process.