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Background: Alzheimer’s disease (AD) is characterized by structural damage, death, and functional disruption of cholinergic neurons (ChNs) as a result of intracellular amyloid-β (Aβ) aggregation, extracellular neuritic plaques, and hyperphosphorylation of protein tau (p-Tau) overtime. Objective: To evaluate the effect of the synthetic cannabinoid CP55940 (CP) on PSEN1 E280A cholinergic-like nerve cells (PSEN1 ChLNs)—a natural model of familial AD. Methods: Wild type (WT) and PSEN1 ChLNs were exposed to CP (1μM) only or in the presence of the CB1 and CB2 receptors (CB1Rs, CB2Rs) inverse agonist SR141716 (1μM) and SR144528 (1μM) respectively, for 24 h. Untreated or treated neurons were assessed for biochemical and functional analysis. Results: CP in the presence of both inverse agonists (hereafter SR) almost completely inhibits the aggregation of intracellular sAβPPβf and p-Tau, increases ΔΨm, decreases oxidation of DJ-1Cys106-SH residue, and blocks the activation of c-Jun, p53, PUMA, and caspase-3 independently of CB1Rs signaling in mutant ChLNs. CP also inhibits the generation of reactive oxygen species partially dependent on CB1Rs. Although CP reduced extracellular Aβ42, it was unable to reverse the Ca2+ influx dysregulation as a response to acetylcholine stimuli in mutant ChLNs. Exposure to anti-Aβ antibody 6E10 (1:300) in the absence or presence of SR plus CP completely recovered transient [Ca2+]i signal as a response to acetylcholine in mutant ChLNs. Conclusion: Taken together our findings suggest that the combination of cannabinoids, CB1Rs inverse agonists, and anti-Aβ antibodies might be a promising therapeutic approach for the treatment of familial AD.

Multi-Target Effects of the Cannabinoid CP55940 on Familial Alzheimer’s Disease PSEN1 E280A Cholinergic-Like Neurons: Role of CB1 Receptor