Alzheimer’s disease (AD) is a neurodegenerative disease associated with neuronal loss and cognitive decline. A neuropathological feature of AD is the deposition of β-amyloid (Aβ) which is proposed to contribute to neuroinflammation and neuronal cell death. A therapeutic approach that can halt the actions of Aβ is a potential strategy to impede disease progression. The orphan G-protein coupled receptor GPR55 is responsive to cannabinoids (Brown & Wise, 2002) and is widely expressed in the neurons and glia of the brain (Henstridge et al. 2011; Pietr et al. 2009). The suggested endogenous ligand for GPR55, L-α-lysophosphatidylinositol (LPI), modulates inflammatory responses (Balenga et al. 2011). This evidence suggests that GPR55 may have a regulatory role in neuroinflammation. The present study aims to examine the role of GPR55 and its signalling pathways in the regulation of neuroinflammation and neuronal cell death using an in vitro model of AD. Cultured primary rat cortical neurons were treated with LPI (1 µM-10 µM). LPI-induced signalling effects were assessed using phospho-cAMP element binding protein (pCREB) immunocytochemistry and confocal microscopy and Fura-2 imaging of intracellular calcium responses. Cortical neurons were also treated with LPI (1 µM) in the presence or absence of Aβ (10 µM) for 72 hours. The conditioned neuronal medium was applied to the BV2 microglial cell line and migration of BV2 cells was assessed using a Boyden chamber assay. Neuronal apoptosis was assessed by caspase-3 immunocytochemistry and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). LPI (10 µM) induced a significant 4-fold increase in CREB phosphorylation after 15 minutes of treatment (p<0.01 vs control, ANOVA and Student Newman-Keuls, n=30 cells measured from 3 independent cultures). LPI (10 µM) induced calcium responses (all results herein are presented as mean±SEM; 0.12±0.05 ratio units, n=30 cells measured from 3 independent cultures). LPI (1 µM) significantly increased levels of migration evoked by Aβ from 1.00±0.00 to 4.55±2.75 (p<0.001 vs control, ANOVA and Student Newman-Keuls, n=4-20). LPI-induced effects on microglial migration were partially blocked by the selective GPR55 antagonist CID16020046 (see Kotsikorou et al. 2013). LPI (10 μM) reduced the number of capase-3 positive neurons evoked by Aβ from 46.79±14.14% to 7.66±5.00%. LPI (10 μM) significantly reduced the number of TUNEL positive neurons evoked by Aβ from 32.89±7.13% to 10.84±3.44% (p<0.05, ANOVA and Student Newman-Keuls, n=500-1000 cells counted from 7-8 independent cultures). This study suggests that LPI can confer a neuroprotective effect and demonstrates a possible role for GPR55 in the regulation of pCREB expression, microglial migration and neuronal apoptosis in an in vitro model of Alzheimer’s disease.