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

Abstract

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 ΔΨ m, 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 Aβ 42, 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.

Role of Cholinergic Signaling in Alzheimer’s Disease

“…In 2012, the French Pharmacoeconomic Committee downgraded the rating of medical benefits provided by AChEIs in AD from “major” to “low” [ 21 ]. In 2018, the French ministry of health decided to delete several items from the available drug reimbursement list of drugs to treat AD symptoms (namely donepezi, rivastigmine, galantamine, memantine) due to the significant side effects, lack of medical benefits and risk [ 113 ]. However, since the causes of AD still remain unclear, AChEIs are still the main drugs in the clinical treatment of AD.…”

Δ8-THC Protects against Amyloid Beta Toxicity Modulating ER Stress In Vitro: A Transcriptomic Analysis

“…Additionally, CB2 agonists, such as JWH-133, showed neuroprotective effects in AD models, reducing inflammation, Aβ plaque and deposition, increasing Aβ clearance and improving cognitive performance [ 34 ]. CP55940, an agonist of CB1 and CB2, restored mitochondrial membrane potential and reactive oxygen species and reduced extracellular Aβ [ 35 ].…”

Latent tri-lineage potential of human menstrual blood-derived mesenchymal stromal cells revealed by specific in vitro culture conditions

“…The stromal cell-based disease model provides a platform for a better understanding of human neurodegenerative disease mechanisms (e.g., [19]) and the potential discovery of innovative therapeutics (e.g., [20]). As primary human neurons from living subjects are normally not accessible to researchers, there is a pressing need for an alternative source of authentic human neurons which allows modeling of neurodegeneration in vitro.…”