Any brain damage including that caused by amyloid triggers
Any MLCK inhibitor peptide 18 damage, including that caused by β-amyloid, triggers activation of microglia, the resident immune cells of the CNS. These cells cluster around amyloid plaques, in which they extend cytoplasmic processes (Combs, 2009). The significance of this response is controversial, but one possibility is that microglia exert an overall beneficial effect, as suggested by behavioral studies showing that microglia depletion or genetic deletions affecting microglia accelerate cognitive decline in a model of AD (i.e., the APP/PS1 transgenic mouse) (Simard et al., 2006, Naert and Rivest, 2011, Song et al., 2011). However, this effect does not seem to be related to the ability of microglia to eliminate parenchymal amyloid plaques, as the latter were not affected (Grathwohl et al., 2009, Mildner et al., 2011) or only modestly (Simard et al., 2006, Tahara et al., 2006, Naert and Rivest, 2011, Song et al., 2011) in the above paradigms. An opposite possibility is that chronically activated microglia exert deleterious effects, for example, by phagocytosing neuronal elements and producing potentially neurotoxic molecules such as TNF (Tan et al., 1999, Tan et al., 2002, Fuhrmann et al., 2010, Lee et al., 2010, Weitz and Town, 2012). Further studies on the molecular mediators responsible for such effects are required to clarify the seemingly dichotomous roles of microglia in AD.
Activated microglia express GPR84, a seven-transmembrane domain receptor of the rhodopsin superfamily that shows limited similarity to other known receptors (Fredriksson et al., 2003, Foord et al., 2005). In the CNS, GPR84 expression is restricted to microglia and observed in different pathological conditions, including EAE, endotoxemia, cuprizone-induced demyelination and axotomy (Bedard et al., 2007, Bouchard et al., 2007, Gamo et al., 2008). In the periphery, GPR84 is mainly expressed by cells of the myeloid lineage, such as monocytes, macrophages and neutrophils (Yousefi et al., 2001, Wang et al., 2006, Suzuki et al., 2013). In vitro studies have revealed that GPR84 signals through a Gi/o pathway in response to hydroxylated (and to a lesser extent nonhydroxylated) medium-chain free fatty acids (FFAs) of 9–14 carbons in length (Wang et al., 2006, Suzuki et al., 2013). These can induce chemotaxis and amplify lipopolysaccharide (LPS)-induced cytokine production in myeloid cells (Wang et al., 2006, Suzuki et al., 2013). Nevertheless, the pathophysiological role of GPR84 and the nature of its endogenous ligand(s) remain unknown.
The goals of the present study were to: (1) examine the expression of GPR84 in APP/PS1 mice; and (2) determine its importance in this model and two others in which GPR84 expression has been reported, i.e., EAE and endotoxic shock (Bouchard et al., 2007). Our results reveal that GPR84 exerts no significant effect on the progression of the latter two diseases, but promotes microgliosis and dendritic homeostasis in APP/PS1 mice. Therefore, this study ascribes for the first time a role to GPR84 in vivo.
Materials and methods
Discussion Two main findings emerge from the present work. First, microglia increase their expression of GPR84 not only upon EAE, endotoxemia and nerve injury, as previously reported (Bedard et al., 2007, Bouchard et al., 2007, Gamo et al., 2008), but also in a neurodegenerative context. GPR84 can therefore be considered as a general “activation” marker for microglia. Second, GPR84 contributes to β-amyloid-induced microgliosis, a response that is required to promote dendritic homeostasis and prevent further cognitive decline. As discussed below, these findings help to understand the role of GPR84 in vivo and the importance of microglia in AD. One question that arises is how microglia protects from β-amyloid toxicity? Our results indicate that GPR84 influences neither the formation or elimination of β-amyloid plaques, nor the concentration of soluble Aβ42, one of the most abundant and toxic form of β-amyloid. This is in agreement with previous studies showing that microglia do not affect the plaques (Grathwohl et al., 2009, Mildner et al., 2011) or at best modestly (Simard et al., 2006, Tahara et al., 2006, Naert and Rivest, 2011, Song et al., 2011). Furthermore, our results reveal a higher number of degenerating dendrites in the absence of GPR84, leading us to infer that a microglial response regulated by GPR84 is required to protect dendrites from further degeneration. Alternatively, it is possible that the absence of GPR84 reduces the ability of microglia to remove degenerating dendrites, which may affect neuronal plasticity and thus cognition. The importance of microglia in neuronal plasticity is increasingly appreciated (Tremblay and Majewska, 2011, Tremblay et al., 2011, Blank and Prinz, 2013, Wake et al., 2013), but further work is needed to elucidate the mechanism by which they influence AD progression.