Cannabinoids have been suggested as potential neuroprotective compounds in Alzheimers disease (AD). Despite intense investigation, the detailed intracellular mechanism(s) involved in cannabinoids survival effect remains to be elucidated. The present study shows that CP55,940 (a CB1 and CB2 agonist) and JWH-015 (a CB2 agonist) protect and rescue peripheral blood lymphocytes (PBL) from (10μM) Aβ [25-35] and (50μM) H2O2-induced apoptosis by two alternative mechanisms: (1) receptor-independent pathway, as demonstrated by no-dihydrorhodamine oxidation into fluorescent rhodamine 123 (R-123) as a result of cannabinoid inhibition of Aβ -generated H2O2; (2) receptor-dependent pathway through NF-κ B activation and p53 down regulation involving phosphoinositide 3-kinase (PI-3K), as demonstrated by using either (25μM) LY294002 (a PI-3K inhibitor),(50nM) pifithrin-α(PFT, a specific p53 inhibitor) or by using immunocytochemistry detection of NF-κ B and p53 transcription factors activation. Importantly, cannabinoid agonists and PFT were able to protect and rescue lymphocytes pre-exposed to toxicants-, even when the three compounds were added up-to 12 h post-Aβ [25-35]/(H2O2) exposure. These results suggest that CP55,940/( JWH-015) protection/rescue of PBL from noxious stimuli is determined by p53 inactivation. These findings may contribute to a better understanding of the role played by cannabinoids as neuroprotective agents to target and interrupt molecular signaling that induce damage in AD disorder.