GPR84 deficiency reduces microgliosis, but accelerates dendritic degeneration and cognitive decline in a mouse model of Alzheimer’s disease

https://doi.org/10.1016/j.bbi.2015.01.010Get rights and content

Highlights

  • The microglial receptor GPR84 promotes microgliosis in APP/PS1 mice, a model of Alzheimer’s disease.

  • Without GPR84, APP/PS1 mice show more dendritic degeneration and accelerated cognitive decline.

  • GPR84 (and therefore microglia) plays a modest, but beneficial role in amyloid pathology.

  • This study reveals for the first time a role of GPR84 in vivo.

Abstract

Microglia surrounds the amyloid plaques that form in the brains of patients with Alzheimer’s disease (AD), but their role is controversial. Under inflammatory conditions, these cells can express GPR84, an orphan receptor whose pathophysiological role is unknown. Here, we report that GPR84 is upregulated in microglia of APP/PS1 transgenic mice, a model of AD. Without GPR84, these mice display both accelerated cognitive decline and a reduced number of microglia, especially in areas surrounding plaques. The lack of GPR84 affects neither plaque formation nor hippocampal neurogenesis, but promotes dendritic degeneration. Furthermore, GPR84 does not influence the clinical progression of other diseases in which its expression has been reported, i.e., experimental autoimmune encephalomyelitis (EAE) and endotoxic shock. We conclude that GPR84 plays a beneficial role in amyloid pathology by acting as a sensor for a yet unknown ligand that promotes microglia recruitment, a response affecting dendritic degeneration and required to prevent further cognitive decline.

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

References (61)

  • M. Suzuki et al.

    Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor

    J. Biol. Chem.

    (2013)
  • R.E. Tanzi et al.

    Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective

    Cell

    (2005)
  • J.Z. Tsien et al.

    The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory

    Cell

    (1996)
  • H. Wake et al.

    Microglia: actively surveying and shaping neuronal circuit structure and function

    Trends Neurosci.

    (2013)
  • M. Arruda-Carvalho et al.

    Posttraining ablation of adult-generated neurons degrades previously acquired memories

    J. Neurosci.

    (2011)
  • J. Audoy-Remus et al.

    Rod-Shaped monocytes patrol the brain vasculature and give rise to perivascular macrophages under the influence of proinflammatory cytokines and angiopoietin-2

    J. Neurosci.

    (2008)
  • A. Bedard et al.

    Identification of genes preferentially expressed by microglia and upregulated during cuprizone-induced inflammation

    Glia

    (2007)
  • K. Belarbi et al.

    Modulation of adult-born neurons in the inflamed hippocampus

    Front. Cell. Neurosci.

    (2013)
  • I. Benilova et al.

    The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes

    Nat. Neurosci.

    (2012)
  • T. Blank et al.

    Microglia as modulators of cognition and neuropsychiatric disorders

    Glia

    (2013)
  • C. Bouchard et al.

    G protein-coupled receptor 84, a microglia-associated protein expressed in neuroinflammatory conditions

    Glia

    (2007)
  • C.D. Clelland et al.

    A functional role for adult hippocampal neurogenesis in spatial pattern separation

    Science

    (2009)
  • C.K. Combs

    Inflammation and microglia actions in Alzheimer’s disease

    J. Neuroimmune Pharmacol.

    (2009)
  • M. Demars et al.

    Impaired neurogenesis is an early event in the etiology of familial Alzheimer’s disease in transgenic mice

    J. Neurosci. Res.

    (2010)
  • W. Deng et al.

    New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?

    Nat. Rev. Neurosci.

    (2010)
  • K. Dikranian et al.

    Ultrastructural studies in APP/PS1 mice expressing human ApoE isoforms: implications for Alzheimer’s disease

    Int. J. Clin. Exp. Pathol.

    (2012)
  • C.T. Ekdahl et al.

    Inflammation is detrimental for neurogenesis in adult brain

    Proc. Natl. Acad. Sci. U.S.A.

    (2003)
  • S.M. Foord et al.

    International Union of Pharmacology. XLVI G protein-coupled receptor list

    Pharmacol. Rev.

    (2005)
  • R. Fredriksson et al.

    The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints

    Mol. Pharmacol.

    (2003)
  • M. Fuhrmann et al.

    Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease

    Nat. Neurosci.

    (2010)
  • Cited by (44)

    • Fatty acid metabolism in the progression and resolution of CNS disorders

      2020, Advanced Drug Delivery Reviews
      Citation Excerpt :

      GPR84 is highly expressed by T cells, neutrophils, macrophages, and microglia [121], and its activation enhances the pro-inflammatory properties of these cells [120,122–126]. Moreover, ample evidence indicates that GPR84 is highly expressed on activated microglia in diverse animal models of CNS pathologies [122,126–128]. Unexpectedly, while GPR84 deficiency reduces microgliosis, it accelerates the number of degenerating dendrites in APP/PS1 mice [128].

    • The role of orphan G protein-coupled receptors in the pathophysiology of multiple sclerosis: A review

      2019, Life Sciences
      Citation Excerpt :

      In agreement with previous findings, Audoy-Remus et al. demonstrated that GPR84 was upregulated in microglia of APP/PS1 transgenic mice, a model of Alzheimer's disease [66]. According to this study, lack of GPR84 did not change plaque formation or hippocampal neurogenesis while it enhanced dendritic degeneration [66]. GPR97 is expressed in leukocytes and has a role both in macrophage-related inflammation and obesity-induced metabolic syndrome [67].

    View all citing articles on Scopus
    View full text