TABLE 5.

Distinct contributions of CB1R or CB2R on in vitro/non-AD models of Alzheimer’s disease-related neuropathology.

Neuropathology	Selective CB1 agonist/CB1-dependent effects	Selective CB2 agonist/CB2-dependent effects
Aβ42 and Tau-p	Arachidonyl-2′-chloroethylamide (ACEA) co-treatment with Aβ42 PREVENTED -Aβ42–-induced changes (↓) in evoked neuronal activity (Haghani et al., 2012). Aβ42 stimulated PC12 neuronal cells and C6 rat glioma cells: ACEA Treatment ↓NO-dependent tau-p (. Esposito et al., 2006a). SH-SY5Y neuroblastoma cells: mRVD-hemopressin (RVD) REVERSED -Apoptosis -Suppression of neurite outgrowth -Suppression of PSD95 -Via INHIBITION of PKA and GSK3b -Effects ablated with CB1 antagonist (Zhang R. et al., 2020). In Vivo STZ exposure In Vitro STZ exposure ACEA ACEA -Reversed Cognitive impairment Modulates STZ-induced NO release ↑ndu-induced Akt/ERK Pathways Rescues cell death ↑ anti-apoptotic proteins (Bcl-2) (Crunfli et al., 2019).	CB2R knockout mice -AD-like tau hyperphosphorylation, ↑ GSK3β activity ↓ of AMPK activity ↓Sirt1 activity ↓mitochondria dysfunction (Wang et al., 2018). HEK293 tau cells (JWH133) ↓ reduces phosphorylation of tau ↓GSK3β activity AMPK-dependent (Wang et al., 2018).
Neuroinflammation, neuronal injury	↓ Aβ42-induced reactive gliosis (Esposito et al., 2007a,2006b). Aβ42 stimulated PC12 neuronal cells and C6 rat glioma cells: ACEA treatment ↓ NO and iNOS expression (Esposito et al., 2006a).
Cognition/BPSD	Rescued memory to baseline after the bilateral Administration of Aβ peptides into the PFC of adult rat (Haghani et al., 2012).	CB2R knockout mice -Hippocampus-dependent memory impairment (Wang et al., 2018).