Table 1.

Pharmacological evidence of CB₂ receptor as a therapeutic target in AD.

References	AD model	Compound acting on CB2 receptors	CB2-mediated effect
Ehrhart et al., 2005	Aβ1−42	JWH-015	↓ IFN-γ-mediated CD40 expression
	Microglial cells culture		↓ TNF-α production
			↑ Phagocytosis of Aβ
			↓ NO
Ramírez et al., 2005	Aβ25−35 and Aβ1−40	HU-210	↑ Neuronal survival
	Microglial rat primary culture	WIN55,212-2	↓ Microglial reactivity to Aβ
	Neuronal rat primary culture	JWH-133	↓ TNF-α levels
	Adult rats (i.c.v. injection)		↑ Cognitive performance
Eubanks et al., 2006	Aβ1−40	Δ9-THC	AchE inhibition
			↓ Aβ aggregation
			(No direct demonstration of CB2 involvement)
Esposito et al., 2006	Aβ1−42	WIN55,212-2	= iNOS levels
	C6 rat glioma cells	JWH015	= NO production
	PC12 neurons	SR144528	= Phosphorylated tau levels
Esposito et al., 2007	Aβ1−42	JWH-015	↑ Aβ-induced astrocytic proliferation (CB2 agonist)
	C6 rat glioma cells	SR144528	↓ Aβ-induced astrocytic proliferation (CB2 antagonist)
	Adult rats (cortical injection)
Tolón et al., 2009	Aβ1−42	JWH-015	↑ Aβ plaque removal
	THP1 human macrophages	SR144528	↑ Aβ Phagocytosis
	U373 human astrocytoma
	Human AD tissue sections
Martín-Moreno et al., 2011	Aβ1−42	JWH-133	↓ ATP-induced increase in [Ca2+]i
	N13 and BV-2 microglial cells	WIN55,212-2	↑ Microglia migration
	Rat primary microglia culture	HU-308	↓ NO production
	Adult mice (i.c.v. injection)	SR144528	↑ Cognitive performance (no direct demonstration of CB2 involvement)
			↓ TNF-α and IL-6 expression (no direct demonstration of CB2 involvement)
Fakhfouri et al., 2012	Aβ1−42	WIN55,212-2	↑ Cognitive performance
	Adult rats (hippocampal injection)	SR144528	↓ TNF-α and nuclear NF-kB levels
			↓ Active caspase 3 levels and TUNEL-positive neurons
Martín-Moreno et al., 2012	TgAPP-2576 mice	JWH-133	↑ Cognitive performance
		WIN55,212-2	↑ Glucose uptake in brain
			↓ Microglial response to Aβ
			↓ Aβ deposition
			↓ TNF-α and COX-2 levels
			↑ Aβ transport across choroid plexus
Aso et al., 2013	APP/PS1 mice	JWH-133	↑ Cognitive performance
			↓ Microglial response to Aβ
			↓ Pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and IFN-γ)
			↓ Tau hyperphosphorylation around plaques
			↓ Oxidative stress damage around plaques
Wc et al., 2013	Aβ1−40	MDA7	↓ Expression of microglia and astrocyte markers
	Adult rats (hippocampal injection)		↓ Secretion of interleukin-1β
			↓ Upsurge of CB2 receptors
			↑ Aβ clearance
			↑ Synaptic plasticity
			↑ Cognitive performance
Bachmeier et al., 2013	Primary human brain microvascular	CB13	↑ Aβ transport across blood brain barrier
	endothelial cells	AM630
	Adult mice (Caudate putamen injection)
Chen et al., 2013	5xFAD APP mice	Δ9-THC	↓ Aβ deposition
			↓ Number of degenerated neurons
			(No direct demonstration of CB2 involvement)
Janefjord et al., 2014	Aβ1−42	JWH-015	↓ Aβ fibrillisation (no direct demonstration of CB2 involvement)
	Neuroblastoma SH-SY5Y cells	Δ9-THC	= Cell viability after Aβ1−42 exposure
	BV-2 microglial cells		↑ Cell viability after LPS exposure
Cao et al., 2014	N2a/APPswe cells	Δ9-THC	↓ Aβ levels
			↓ Aβ aggregation
			↓ Tau phosphorylation
			↑ Mitochondria function
			(No direct demonstration of CB2 involvement)
Aso et al., 2015	APP/PS1 mice	Δ9-THC	↑ Cognitive performance
			↓ Astroglial response to Aβ
			(No direct demonstration of CB2 involvement)
Köfalvi et al., 2016	TgAPP-2576 mice	JWH-133	↑ Glucose uptake in brain
		WIN55,212-2
		AM630