Table 1.
Reported microglial-G protein-coupled receptors (GPCRs) and their role in Alzheimer’s disease (AD).
| Microglial GPCRs | Sub-types | Endogenous modulators | Synthetic modulators | Mechanism | Role in AD | Reference |
|---|---|---|---|---|---|---|
| nAChR | α7 nAChRs | Aβ, Choline, Kynurenic acid | Galantamine | ↑NO, ↑TNF-α expression and ↑IL-6 activation induces ↑Ca2+ influx, ↑Calmodulin-CaMKII pathway | ↑Aβ clearance through microglia phagocytosis | Takata et al. (2010) and Steiner et al. (2014) |
| mAchRs | M1 | Dopamine | Carbachol, Aβ(40, 42 and 25), AF267, Dicyclomine, C-2 ceramide | ↑PKC-α, ↑PKC-γ and/or ↑CREB, ↑pMAPK | ↑α-secretase, ↑sAPP release and P3, ↑Aβ generation | Buxbaum et al. (1992); Hung et al. (1993); Farber et al. (1995); Caccamo et al. (2006); Joseph et al. (2006) and Joseph et al. (2007) |
| Adenosine | A1 | ATP, Adenosine | Caffeine, DPCPX, SCH58261 | ↓Ca2+ influx, ↑Cyclic nucleotide signaling, ↑p21 Ras activation, ↑ERK1/2 phosphorylation | ↓Microglial activation, ↑neuronal damage ↑phosphorylation and translocation of tau, ↑Aβ toxicity | Schubert et al. (2000); Angulo et al. (2003); Giunta et al. (2014); and Luongo et al. (2014) |
| A2A | Adenosine | Caffeine, DPCPX, SCH58261 | ↑Cyclic nucleotide signaling | ↑Neuronal damage, ↑Aβ toxicity | Schubert et al. (2000) and Giunta et al. (2014) | |
| A2B | Adenosine | MRS1754, BAY60-6583 | ↑IL-6 and ↑IL-10, ↑p38 MAPK, ↑pCREB | ↓Microglia activation | Koscsó et al. (2012) and Merighi et al. (2017) | |
| A3 | Adenosine | Cl-IB-MECA, and MRS1523 | ↓PI3 kinase/Akt, ↓NF-κB and ↓TNF-α | ↓Microglia activation | Hammarberg et al. (2003) and Lee et al. (2006) | |
| Purinergic | P2Y2 | ATP and UTP | ↑Nox | ↑Aβ degradation and clearance | Kim et al. (2012); Mead et al. (2012) and Ajit et al. (2014) | |
| P2Y4 | ATP | ↑Nox, the ↑PI 3-kinases/Akt cascade | ↑Microglial uptake of Aβ | Mead et al. (2012) and Li et al. (2013) | ||
| P2Y6 | UDP | MRS2578 | ↑NFATc1, ↑c2, ↑CCL2 and CCL3 production | ↑Microglial chemotaxis, ↑Microglial phagocytosis | Koizumi et al. (2007) and Kim et al. (2011) | |
| P2Y12 | ADP | ↑cAMP-dependent PKA | ↑Microbial chemotaxis | Nasu-Tada et al. (2005) | ||
| P2Y13 | ADP | ↑cAMP-dependent PKA | ↑Microbial chemotaxis | Nasu-Tada et al. (2005) | ||
| mGluRs | Group I (mGluR1 and mGluR5) | Triptolide (T10), CHPG, MTEP and VU0360172 | ↓iNOS, TNF-α, and IL-1β and IL-6 and MAPKs pathway, ↑Shedding of the microvesicle from microglia, ↑Microglia-induced astrocyte | ↓Microglial-mediated neurotoxicity, modulate microglia-neuron communication | Beneventano et al. (2017) and Huang et al. (2018) | |
| Group II (mGluR2 and mGluR3) | LYY37926, (RS)-α-methyl-4-sulphonophenylglycine | mGluR2: ↑TNF-α release and caspase-3 activation and FasL expression, mGluR3:↑BDNF | mGluR2: ↑Microglial neurotoxicity, ↑sAPPα, ↑Non-amyloidogenic cleavage of APP. mGluR3: ↑sAPPα and ↓Amyloid level. Switching of microglial phenotype to neurotoxic phenotype | Kingham et al. (1999); Taylor et al. (2002); Taylor et al. (2003); Durand et al. (2014) and Durand et al. (2017) | ||
| Group III (mGluR4, mGluR6, mGluR7 and mGluR8) | (L)-2-amino-4-phosphono-butyric acid (L-AP-4), (R, S)-phosphonophenylglycine (RS-PPG) | ↓Microglial glutamate release, ↓Excitotoxicity, ↑Astrocytic glutamate | ↓Microglia-mediated neurotoxicity | Taylor et al. (2003) | ||
| Adrenergic | α2A | Nonspecific Atipamezole, BRL-44408 and Dexmedetomidine (DEX) | ↓TLR4 overexpression, ↓IL-4, ↓Arg-1, ↓Resistin-like α (Retnla/Fizz1), and ↓Chitinase 3-like 3 (Chi3l3/Ym1) expression | ↓Cognitive impairment, ↓Polarization of microglia to M1 | Yamanaka et al. (2017) and Zhang et al. (2017) | |
| β1 | . | Xamoterol and STD-101-D1 | ↓Iba1 and GFAP, ↓(Iba1, CD74, CD14 and TGFβ), ↓TNF-α | ↓Microgliosis | Ni et al. (2006); Yu et al. (2011) and Ardestani et al. (2017) | |
| β2 | Isoproterenol | ↑α secretase activity, ↑Aβ level | Ni et al. (2006) | |||
| FPRL1/2 | Aβ42 | Aβ42, Annexin A1 (ANXA1), Humanin, palmitoyl-cys[(RS)-2, 3-di(palmitoyloxy)-propyl]-Ala-Gly-OH (PamCA), and muramyl dipeptide (MDP) | ↑TNF-α and ↑MAPK p38 | ↑Microglial chemotaxis, ↓Aβ level | Cui et al. (2002); Ying et al. (2004); Iribarren et al. (2005); and Ries et al. (2016) | |
| CMKLR1 | Aβ42 | ↑ERK1/2, PKA, and Akt | ↑Processing and clearance of Aβ42 | Peng et al. (2015) | ||
| Chemokine receptors | CCR5 CX3CR1 | CCL2 CCL3 CCL4 CXCL8 | NA | Associated with amyloid deposits, ↓Microglial neurotoxicity, ↓γ-secretase activity | Xia et al. (1998); Bakshi et al. (2008) and Hickman and El Khoury (2010) | |
| Cannabinoid receptors | CB1 | Endocannabinoids | Tetrahydrocannabinol (THC), Agonist: HU-210, WIN55, 212–2, and JWH-133 | ↓NADPH oxidase reactive oxygen species, ↓IL-1β and TNF-α and NO | CB1 expression decreased as AD progresses | Howlett et al. (1986); Glass and Felder (1997); Ramírez et al. (2005); and Manuel et al. (2014) |
| CB2 | Endocannabinoids | Tetrahydrocannabinol (THC), Agonist: AM1241, HU-210, WIN55, 212–2, and JWH-133 Antagonist: AM630 | ↓IL-6, TNF-α and free radical production | ↓Aβ-induced microglial activity | Howlett et al. (1986); Glass and Felder (1997); Facchinetti et al. (2003); Walter et al. (2003); Carrier et al. (2004); Ramírez et al. (2005); Eljaschewitsch et al. (2006); Bisogno and Di Marzo (2010); and Ma et al. (2015) | |
| GPR55 | Lysophophatidylinositol (LPI) | Abnormal-cannabidiol (Abn-CBD), Antagonist: CID16020046 | ↑ERK phosphorylation | Involved in spatial learning and memory, motor function, memory formation and neuroinflammation | Brosnan and Brosnan (2013) and Stojanovic et al. (2014). | |
| Orphan GPCRs | GPR18 | N-arachidonoyl glycine (NAGly) | ↑MAPK activation | ↑Microglial migration to neuronal damage | McHugh et al. (2010) |
Up arrow denote increase and the down arrow denotes decrease.