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    • The formation of SGs in

    2018-10-30

    The formation of SGs in MG in response to low levels of either SA or Aβ requires the activity and expression of SYK as it is blocked by SYK inhibitors or by a knockdown or reduction of SYK expression. In inflammatory cells like MG, SYK plays a well known role in the receptor-mediated production of ROS and RNS (Yi et al., 2014). Aβ binds to MG via an pteryxin of cell surface receptors (Mosher and Wyss-Coray, 2014) many of which, including CD14, TLR4, CD36, and SIRPβ1, are coupled to SYK either directly or through receptor-associated proteins that contain ITAMs (Miller et al., 2012; Heit et al., 2013; Gaikwad et al., 2009; Dietrich et al., 2000; Bamberger et al., 2003). The interactions of microglial cells with Aβ leads to the phosphorylation and activation of LYN and SYK, which are coupled to the generation of superoxide radicals and lead to neurotoxicity (McDonald et al., 1997; Combs et al., 1999; Sondag et al., 2009). SYK also is activated in cells under conditions of increased oxidative stress (Schieven et al., 1993). The resulting SYK-dependent pro-inflammatory response may be further exacerbated by the retention within SGs of active SYK—as reflected by the presence of phosphotyrosine-containing proteins—which may continue to stimulate downstream signaling pathways that generate ROS or RNS. The production of ROS and RNS can be damaging to neighboring cells (Mosher and Wyss-Coray, 2014) and we find, in fact, that chronically activated MG produce mediators that are toxic to HT22 neuronal cells. Consistent with a role for SYK in these processes, the generation of chronically activated MG that produce ROS and RNS and the ability of these cells to kill neuronal cells are all blocked by SYK inhibitors. Interestingly, chronically stressed MG also produce increased quantifies of IFNγ and MCP-1/CCL2, cytokines reported previously to be produced by MG in response to stress associated with Parkinson\'s disease or inflammation (Barcia et al., 2012; D\'Mello et al., 2009). The ability of MG to clear Aβ plaques through phagocytosis is important for the control of AD (Bamberger et al., 2003; El Khoury et al., 2007). Chronic stress induced by prolonged exposure of MG to either SA or Aβ inhibits the ability of these cells to phagocytose either bacteria or Aβ fibrils. Since the chronic stimulation of MG with either SA or Aβ results in the formation of very large SGs to which SYK is recruited, we propose that it is the sequestration of the kinase away from phagocytic receptors that underlies the impaired phagocytic activity of MG. An enhanced accumulation of Aβ plaques in the brain would be an expected result of exposure to oxidative stress due to this loss of phagocytic activity of stressed MG. The exposure of MG to Aβ or Aβ fibrils alone also induces the appearance of abundant SGs, consistent with the known ability of Aβ to trigger MG cell activation and promote the generation of ROS and RNS (Bianca et al., 1999; Combs et al., 2001). Thus, a defect in the removal of Aβ fibrils by MG compromised by oxidative stress could cause a build-up of Aβ plaques leading to additional Aβ-induced stress and the enhanced formation of persistent SGs. In a mouse model of AD, the phagocytic activity of MG is selectively compromised in brain regions containing Aβ plaques (Krabbe et al., 2013). This would be particularly problematic in aged brains as our evidence indicates that MG from older mice are more sensitive to Aβ-induced formation of SGs. The critical role that SYK plays in modulating immune cell signaling pathways has generated considerable interest in the development of inhibitors of SYK for the treatment of inflammatory diseases (Geahlen, 2014) including, recently, Alzheimer\'s disease (Paris et al., 2014). While SYK inhibitors might reasonably be expected to reduce the activation of MG and production of inflammatory mediators, inhibitors also block phagocytosis. This may complicate the development of strategies for the use of specific SYK inhibitors for the treatment or prevention of AD. However, the finding that active SYK is sequestered in SGs suggests that strategies to relocate the enzyme might be effective in restoring some function to damaged MG. We find that the treatment of chronically stressed MG with rabbit IgG leads to a dramatic restoration of phagocytic activity. The recovery of activity is not a function of the reactivity of the IgG to any specific antigen as even an affinity-purified antibody prepared against a peptide found on the cytoplasmic domain of an ITIM-containing receptor is able to induce this effect. Treatment of MG with IgG leads to a relocalization of SYK from the cytoplasm to the plasma membrane in unstressed cells and from SGs to the membrane in chronically stressed cells. This effect may help explain the therapeutic benefits of intravenous immunoglobulins (IVIg), which have shown efficacy in slowing the progression of AD in some human clinical trials (Dodel et al., 2002; Dodel et al., 2004; Relkin et al., 2009; Loeffler, 2013). The benefits of IVIg are generally attributed to the presence of anti-Aβ antibodies in the pooled IgG preparations (Dodel et al., 2004). However, it is interesting to note that the administration of pooled mouse IgG having no detectable anti-Aβ activity to the brains of APP/PS1 mice leads to a reduction in Aβ deposits similar to IVIg (Sudduth et al., 2013). Thus, even immunoglobulins that fail to recognize Aβ have the potential to reverse defects in the function of stressed MG. This observation suggests that the development of IgG-related therapeutics optimized for the recovery of phagocytic activity of MG would be an attractive strategy for augmenting current strategies for the treatment of AD.