TABLE 3.

Influence of CBD/THC on in vitro/non-ad models of Alzheimer’s disease-related neuropathology.

Neuropathology	CBD	Cannabinoid system modulators (CB1 and CB2 Activators; ECB Reuptake Inhibitors, THC + CBD Combined Treatment)
Aβ 42 and Tau-p	↓Aβ neurotoxicity via inhibiting caspase-3 (Haghani et al., 2012). Ab42 stimulated PC12 neuronal cells ↓Ab-induced tau-p ↓GSK3b ↑ Wnt/b-catenin pathway ↑ APP ubiquitination ↓Ab42 Via stimulation of PPARg (Vallee et al., 2017). ↓tau-hyper-p Rescue mediated by Wnt/b-catenin pathway (Esposito et al., 2006c). Ab42 stimulated PC12 neuronal cells and C6 rat glioma cells: ↓NO-dependent tau-p (Esposito et al., 2006b).	Ab42 stimulated PC12 neuronal cells and C6 rat glioma cells: WIN-55,212-2 ↓NO-dependent tau-phosphorylation (Esposito et al., 2006a). Ab42 stimulated hippocampal neuronal and glial co-cultures: URB 602 or JZL184; MAGL Inhibitors ↑s-AG ↓ Ab42-induced neurodegeneration and apoptosis ↓ ERK1/2, NFkb phosphorylation (Chen et al., 2011). Traumatic brain injury PF04457845 (FAAH Inhibitor) ↑)EA ↓tau phosphorylation ↓GSK-3b phosphorylation ↓p35/25 (caspase cleavage products) (Selvaraj et al., 2019).
Neuroinflammation, neuronal injury	↓ Inflammation ↓ GFAP and iNOS expression ↓ nitrites, and IL-1b (Esposito et al., 2007a). ↓ reactive gliosis ↓ neuronal damage Effects dependent on PPARg interaction (Esposito et al., 2011). Ab42 stimulated PC12 neuronal cells and C6 rat glioma cells: ↓NO-dependent tau-phosphorylation ↓ nitrite production ↓iNOS expression Inhibition of p-38 Inhibition of MAPK Inhibition of NFkB (Esposito et al., 2006b). Ab42 stimulated PC12 neuronal cells ↓oxidative stress ↓mitochondrial dysfunction ↓Reactive Oxygen Species (ROS) (Vallee et al., 2017).	Ab42 stimulated PC12 neuronal cells and C6 rat glioma cells: WIN-55,212-2 ↓ NO and iNOS expression (Esposito et al., 2006a). Prevents inflammatory activation, loss of neuronal markers, and cognitive deficits in Aβ-treated rats (Ramírez et al., 2005). Traumatic brain injury Cannabinoids, via activation of CB1R/CB2R are: -neuroprotective against excitotoxicity and acute brain damage both in vitro and in vivo -via blockade of excitotoxicity -reduction of calcium influx -antioxidant properties -enhanced trophic factor support (van der Stelt et al., 2002; Mechoulam and Shohami, 2007). PF04457845 (FAAH Inhibitor) ↑)EA ↓IL1-b, IL-6 and TNF-a (Selvaraj et al., 2019).

(Ramírez et al., 2005; Esposito et al., 2006a,b,c, 2007a,b, 2011; van der Stelt et al., 2006; Chen et al., 2011; Vallee et al., 2017; Selvaraj et al., 2019).