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The Potential Therapeutic Effects of THC on Alzheimer's Disease

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The Potential Therapeutic Effects of THC on Alzheimer's Disease

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The purpose of this study was to investigate the potential therapeutic qualities of Δ9-tetrahydrocannabinol (THC) with respect to slowing or halting the hallmark characteristics of Alzheimer's disease. N2a-variant amyloid-β protein precursor (AβPP) cells were incubated with THC and assayed for amyloid-β (Aβ) levels at the 6-, 24-, and 48-hour time marks. THC was also tested for synergy with caffeine, in respect to the reduction of the Aβ level in N2a/AβPPswe cells. THC was also tested to determine if multiple treatments were beneficial. The MTT assay was performed to test the toxicity of THC. Thioflavin T assays and western blots were performed to test the direct anti-Aβ aggregation significance of THC. Lastly, THC was tested to determine its effects on glycogen synthase kinase-3β (GSK-3β) and related signaling pathways. From the results, we have discovered THC to be effective at lowering Aβ levels in N2a/AβPPswe cells at extremely low concentrations in a dose-dependent manner. However, no additive effect was found by combining caffeine and THC together. We did discover that THC directly interacts with Aβ peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3β levels and phosphorylated GSK-3β in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin's enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer's disease through multiple functions and pathways.
(A) A western blot performed to determine the effects of THC on GSK-3 in N2a/APPswe.-actin was used as a control to indicate that the expression rate was constant. The left indicator is molecular weight. Lane 1, 2, and 3 are-actin level and lane 4, 5, and 6 are GSK-3 expression. 1 and 4 are cell controls, 2 and 5 are cells treated with 2.5 nM THC, and lane 3 and 6 are cells treated with 0.25 nM THC. THC can inhibit GSK-3 level at 2.4 nM concentration, (B) Graph representing the expression decrease in GSK-3 in a dose-dependent manner by using-actin to obtain a value for the ratio of expressed GSK-3. As shown in the bar graph, the total GSK-3 decrease after using-actin standardized protein loading, (C) GSK-3 expression in N2a/APPswe treated with different drugs: Cells were plated in 6 well plate for overnight and then drugs were added into each designated wells in duplicate. Cells were lysed after 36 hours incubation. Proteins were loaded onto SDS-page gel and then blotted with each antibody after transfer onto PVDF membrane. Groups are: CTRL, Control; M1T2, 10 −5 M Melatonin + 2.5 nM THC; M2T2, 10 −6 M Melatonin + 2.5 nM THC; T1, THC 25 nM; T2, THC 2.5 nM; T3, THC 0.25 nM, (D) Expression of pGSK-3 following melatonin and THC treatment in N2a/APPswe cells. *The same batch protein samples were used in this test as in Fig. 7C. Bands were quantified. One-way ANOVA was applied to the data. p < 0.05 when compared with control group. **p < 0.01 when compared with control group. Groups are: Ctrl, Control; M1T2, 10 −5 M Melatonin + 2.5 nM THC; M2T2, 10 −6 M Melatonin + 2.5 nM THC; T1, THC 25 nM; T2, THC 2.5 nM; T3, THC 0.25 nM.
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... Nonetheless, treatment with 0.2 mg/kg THC significantly increased the Aβ monomer level and decreased the Aβ oligomer level in APP/PS1 mouse brain homogenates (Figure 6). Given the overall observations in this study as well as the results of our previous thioflavin T fluorescence assay showing the inhibitory effect of THC on Aβ1-40 aggregation in vitro [24], it is speculated that low-dose THC treatment has the potential to reduce amyloid deposits in the brain by preventing the aggregation of Aβ monomers and the formation of Aβ oligomers. Further studies are warranted to investigate the effect of THC on the polymerization process of Aβ through direct monitoring of the Aβ monomer to oligomer transition in vivo using fiber-based fluorescence correlation stereoscopy [44]. ...
... In this study, we observed that treatment of THC at 0.2 mg/kg significantly decreased not only the Aβ oligomer level but also the phospho-tau and total tau levels in APP/PS mouse brain tissues (Figures 6D and 7). This finding is in line with our previous observation that THC treatment inhibited Aβ aggregation in vitro and suppressed phosphorylated Tau production in cultured N2a/APPswe cells [24]. One possibility would be that THC treatment interrupts the pathological feedback loop between Aβ and tau. ...
... Our previous in vitro study showed that THC treatment increased the rate of mitochondrial oxygen consumption [24]. Therefore, we evaluated the effect of in vivo THC treatment on modulating the brain expression of TFAM, CKMT1, and MFF proteins, which are prominent effectors involved in genome maintenance, energy metabolism, and mitochondrial fission process [37][38][39]. ...
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Studies on the effective and safe therapeutic dosage of delta-9-tetrahydrocannabinol (THC) for the treatment of Alzheimer’s disease (AD) have been sparse due to the concern about THC’s psychotropic activity. The present study focused on demonstrating the beneficial effect of low-dose THC treatment in preclinical AD models. The effect of THC on amyloid-β (Aβ) production was examined in N2a/AβPPswe cells. An in vivo study was conducted in aged APP/PS1 transgenic mice that received an intraperitoneal injection of THC at 0.02 and 0.2 mg/kg every other day for three months. The in vitro study showed that THC inhibited Aβ aggregation within a safe dose range. Results of the radial arm water maze (RAWM) test demonstrated that treatment with 0.02 and 0.2 mg/kg of THC for three months significantly improved the spatial learning performance of aged APP/PS1 mice in a dose-dependent manner. Results of protein analyses revealed that low-dose THC treatment significantly decreased the expression of Aβ oligomers, phospho-tau and total tau, and increased the expression of Aβ monomers and phospho-GSK-3β (Ser9) in the THC-treated brain tissues. In conclusion, treatment with THC at 0.2 and 0.02 mg/kg improved the spatial learning of aged APP/PS1 mice, suggesting low-dose THC is a safe and effective treatment for AD.
... THC has also been found to inhibit several AD-related pathologies. For example, in vitro studies showed that THC dose-dependently removed and inhibited the aggregation of Aβ in neuro2a Swedish variant APP cells (Cao et al., 2014) and in induced MC65 cells (Currais et al., 2016;Schubert et al., 2019) and protected against excitotoxicity and oxidative stress in mouse neuronal cells (Marsicano et al., 2002). Furthermore, 80% THC cannabis extract was 60% effective in reducing Aβ 42 +Cu (II)-induced ROS in SH-SY5Y cells (Raja et al., 2020). ...
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Alzheimer’s disease (AD) is a debilitating neurodegenerative disease characterized by declining cognition and behavioral impairment, and hallmarked by extracellular amyloid-β plaques, intracellular neurofibrillary tangles (NFT), oxidative stress, neuroinflammation, and neurodegeneration. There is currently no cure for AD and approved treatments do not halt or slow disease progression, highlighting the need for novel therapeutic strategies. Importantly, the endocannabinoid system (ECS) is affected in AD. Phytocannabinoids, including cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), interact with the ECS, have anti-inflammatory, antioxidant, and neuroprotective properties, can ameliorate amyloid-β and NFT-related pathologies, and promote neurogenesis. Thus, in recent years, purified CBD and THC have been evaluated for their therapeutic potential. CBD reversed and prevented the development of cognitive deficits in AD rodent models, and low-dose THC improved cognition in aging mice. Importantly, CBD, THC, and other phytochemicals present in Cannabis sativa interact with each other in a synergistic fashion (the “entourage effect”) and have greater therapeutic potential when administered together, rather than individually. Thus, treatment of AD using a multi-cannabinoid strategy (such as whole plant cannabis extracts or particular CBD:THC combinations) may be more efficacious compared to cannabinoid isolate treatment strategies. Here, we review the current evidence for the validity of using multi-cannabinoid formulations for AD therapy. We discuss that such treatment strategies appear valid for AD therapy but further investigations, particularly clinical studies, are required to determine optimal dose and ratio of cannabinoids for superior effectiveness and limiting potential side effects. Furthermore, it is pertinent that future in vivo and clinical investigations consider sex effects.
... ∆9-tetrahydrocannabinol (THC), which is the major psychoactive constituent of the cannabis plant, potentially affects many of the factors involved in AD pathologies, such as Aβ clearance, mitochondrial function, inflammation, and neurogenesis [5,6]. Indeed, in vitro, THC decreases Aβ concentration in a dose-dependent manner in N2a/APPswe cells [7]. In vivo, treatment with THC reduces the Aβ burden in 5XFAD/APP mice [8] and reduces neuronal loss and restores cerebral glucose metabolism in the hippocampus of a mouse model of sporadic AD [9]. ...
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Alzheimer’s disease (AD) is the most common form of dementia, but there is still no available treatment. Δ9-tetrahydrocannabinol (THC) is emerging as a promising therapeutic agent. Using THC in conventional high doses may have deleterious effects. Therefore, we propose to use an ultra-low dose of THC (ULD-THC). We previously published that a single injection of ULD-THC ameliorated cognitive functioning in several models of brain injuries as well as in naturally aging mice. Here, 5xFAD AD model mice received a single treatment of ULD-THC (0.002 mg/kg) after disease onset and were examined in two separate experiments for cognitive functions, neurotropic, and inflammatory factors in the hippocampus. We show that a single injection of ULD-THC alleviated cognitive impairments in 6- and 12-month-old 5xFAD mice. On the biochemical level, our results indicate an imbalance between the truncated TrkB receptor isoform and the full receptor, with AD mice showing a greater tendency to express the truncated receptor, and ULD-THC improved this imbalance. We also investigated the expression of three AD-related inflammatory markers and found an ameliorating effect of ULD-THC. The current research demonstrates for the first time the beneficial effects of a single ultra-low dose of THC in a mouse model of AD after disease onset.
... The anti-inflammatory properties of THC may help to protect the brain against neurodegenerative diseases [40]. Indeed, while high doses of THC can cause memory deficits [41], low doses of THC have been shown to slow or halt Alzheimer's disease (AD) progression by reducing the amyloid beta, which is the main component of the amyloid plaques found in the brains of people affected by AD [42,43], and to restore cognitive function in old mice [44]. Taken together, these findings reinforce the suggestion that the THC doses and patient age determine the beneficial versus detrimental effects of THC on neuronal health [27]. ...
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For centuries, the cannabis plant has been used as a source of food, fiber, and medicine. Recently, scientific interest in cannabis has increased considerably, as its bioactive compounds have shown promising potential in the treatment of numerous musculoskeletal and neurological diseases in humans. However, the mechanisms that underlie its possible effects on neurodevelopment and nervous-system functioning remain poorly understood and need to be further investigated. Although the bulk of research on cannabis and cannabinoids is based on in vitro or rodent models, the zebrafish has now emerged as a powerful in vivo model for drug-screening studies and translational research. We here review the available literature on the use of cannabis/cannabinoids in zebrafish, and particularly in zebrafish models of neurological disorders. A critical analysis suggests that zebrafish could serve as an experimental tool for testing the bioactivity of cannabinoids, and they could thus provide important insights into the safety and efficacy of different cannabis-extract-based products. The review showed that zebrafish exhibit similar behaviors to rodents following cannabinoid exposure. The authors stress the importance of analyzing the full spectrum of naturally occurring cannabinoids, rather than just the main ones, THC and CBD, and they offer some pointers on performing behavioral analysis in zebrafish.
... We hypothesize that the apoptosis of A549 cells treated with THC or CBN is caused by decreased phosphorylation of AKT, which results in decreased phosphorylation of GSK-3α/β. Indeed, this has been confirmed by a previous study where it was found that THC decreased the level of phosphorylated GSK-3β [19]. ...
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Objective: To investigate the effects of Δ9-tetrahydrocannabinol, the principal psychoactive compound of Cannabis sativa, and cannabinol, a Δ9-tetrahydrocannabinol degradative product, on human non-small cell lung cancer cells. Methods: Δ9-Tetrahydrocannabinol and cannabinol were tested for anticancer activity in human non-small cell lung cancer (A549) cells. The effects on cell proliferation, apoptosis, and phosphorylation profiles were examined. The effects of Δ9-tetrahydrocannabinol and cannabinol on tumor growth were also investigated using a xenograft nude mouse model. Apoptosis and targeted phosphorylation were verified by immunohistochemistry. Results: Δ9-Tetrahydrocannabinol and cannabinol significantly inhibited cell proliferation and increased the number of apoptotic cells in a concentration-dependent manner. The Δ9-tetrahydrocannabinol- and cannabinol-treated cells had lower levels of phosphorylated protein kinase B [AKT (S473)], glycogen synthase kinase 3 alpha/beta, and endothelial nitric oxide synthase compared to the controls. The study of xenograft mice revealed that tumors treated with 15 mg/kg Δ9-tetrahydrocannabinol or 40 mg/kg cannabinol were significantly smaller than those of the control mice. The tumor progression rates in mice treated with 15 mg/kg Δ9-tetrahydrocannabinol or 40 mg/kg cannabinol were significantly slower than in the control group. Conclusions: These findings indicate that Δ9-tetrahydrocannabinol and cannabinol inhibit lung cancer cell growth by inhibiting AKT and its signaling pathways, which include glycogen synthase kinase 3 alpha/beta and endothelial nitric oxide synthase.
... In fact, myriad papers have reported cannabinoid effects on AD using experimental in vitro and in vivo models. For instance, cannabinoid treatment attenuates Aβ and neurofibrillary tau accumulation, as well as memory deficits in AD transgenic mouse models [34,35]; blocks Aβ neuronal proteolysis and prevents Aβ aggregation [36]; mitigates Aβ-induced neuroinflammation and oxidative stress [37]; whereas favoring neurogenesis factors [that is, brain-derived neurotrophic factor (BDNF)] and antiinflammatory cytokine release, as well as presynaptic and axonal proteins upregulation [10,34,[37][38][39][40][41][42][43][44][45]. Thus, we are also hypothesizing that the long-term positive effects of the cannabinoid extract may be due to reduction in AD-related neuroinflammation. ...
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... However, the active ingredient in marijuana (i.e., THC) is a competitive inhibitor of acetylcholinesterase, a critical region involved in the formation of Aβ (Eubanks et al., 2006). Therefore, it is shown that low doses of marijuana may have therapeutic effects on AD (Cao et al., 2014). ...
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... Cannabis contains more than 100 kinds of cannabinoid compounds with the major classes being ∆9-trans-tetrahydrocannabidiol (THC) and cannabidiol (CBD). The neuroprotective effect of THC against iAβ accumulation has already been evidenced in several drug screening studies [43,128,129]. However, due to the psychoactive properties of THC, other non-psychoactive classes of cannabinoids, as well as artificial cannabinoids, have been tested as more suitable treatment options, and recent reports were able to demonstrate promising neuroprotective effects with an especially prominent effect on the reduction in iAβ [43,128,130]. ...
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01-02-02 The goal was to forecast the global burden of Alzheimer’s disease and evaluate the potential impact of interventions that delay disease onset or progression.
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