GPR84 deficiency reduces microgliosis, but accelerates dendritic degeneration and cognitive decline in a mouse model of Alzheimer’s disease
Introduction
The amyloid cascade hypothesis states that altered processing of amyloid precursor protein lead to the release of β-amyloid peptides (e.g., Aβ42), which initiate the pathological process underlying AD (Tanzi and Bertram, 2005). These peptides can aggregate into soluble oligomers and then into insoluble fibrils that accumulate to form macroscopic amyloid plaques. Whether all of these forms are toxic and how they cause toxicity are questions that are still debated. A prevailing view is that the oligomers, more toxic than the fibrils, bind to and alter the function of certain membrane proteins, resulting in synaptic dysfunction, dendritic degeneration and neuronal death (Benilova et al., 2012).
Any brain 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.
Section snippets
Animals
GPR84-deficient mice were obtained from DeltaOne (Deltagen) and bred with C57BL/6 J mice (Jackson Laboratory) for at least 5 generations. These mice are reported to be indistinguishable from wild-type littermates under normal conditions (Venkataraman and Kuo, 2005). APP/PS1 transgenic mice (Borchelt et al., 1997) (Jackson Laboratory, B6C3-Tg(APP695)3Dbo Tg(PSEN1)5Dbo/J) expressing a chimeric amyloid precursor protein (APPSwe) and human presenilin 1 (A246E variant) under the control of the mouse
GPR84 is upregulated in microglia of APP/PS1 mice
We have reported that GPR84 is upregulated in microglia under the control of TNF and IL-1β and during different pathological conditions such as EAE and endotoxemia (Bedard et al., 2007, Bouchard et al., 2007). To test our assumption that GPR84 would also be expressed in a neurodegenerative context, we analyzed, by in situ hybridization, brain sections from APP/PS1 transgenic mice killed at different ages. This technique was used because reliable immunostaining for GPR84 could not be achieved
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
Conflict of interest
No conflict of interest is declared by the authors.
Acknowledgments
This work was supported by grants from the Canadian Institutes for Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada and the Multiple Sclerosis Society of Canada. L.V. and S.L. received Chercheur-Boursier Sénior awards from the Fonds de recherche du Québec – Santé. JAR was supported by a CIHR Strategic Training Program Grant in genomics. L.B. received a Merit Scholarship from the Fonds de recherche du Québec – Nature et technologies. MET was funded by the
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