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The Potential Therapeutic Effects of THC on Alzheimer's Disease
Journal of Alzheimer's Disease
Abstract and Figures
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.
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... that CBD, THC, and their mixtures can decrease the pathological hallmarks of AD ( Table 1). Treatment with THC decreased the aggregation of Aβ proteins, reduced the levels of GSK3 beta protein (an enzyme responsible for tau phosphorylation), and improved mitochondrial activity in N2a/APPswe cells [75]. In addition, administering THC to aged APP/PS1 mice at doses of 0.2 and 0.02 mg/kg daily over three months enhanced cognitive abilities, namely, in their capacity to acquire novel knowledge within their surroundings. ...
... As a result of malfunctioning mitochondria, excessive ROS build up and ATP is depleted [91]. In vitro studies have shown that low doses of THC enhance mitochondrial function in N2a-variant Aβ protein precursor (AβPP) cells [75]. However, at higher doses, THC is detrimental to brain mitochondrial respiratory chain dysfunction and increases oxidative stress [92]. ...
... The study conducted by Cao et al. [56] explored the potential therapeutic benefits of THC in N2a/AβPPswe cells. Through a series of experiments, they established a time-dependent (6h, 24h, 48h) and dose-dependent (0.25nM, 2.5nM, 25nM, 250nM, 2500nM) relationship between THC administration and the reduction of Aβ40 levels. ...
... Moving to non-selective CB1R/CB2R agonists, this category includes natural cannabinoids such as THC, CBD, THCA/CBDA, and various Cannabis extracts. THC studies yielded conflicting results, with some showing reductions in Aβ40 production and TAU phosphorylation possibly through mitigating ER stress [56,57], while others found no significant difference compared to controls, possibly due to methodological considerations [58]. To account for the observed Hawthorne or instudy effect [84], an individually randomized crossover study design may prove beneficial. ...
Alzheimer's disease (AD), a progressive neurodegenerative disorder, manifests through dysregulation of brain function and subsequent loss of bodily control, attributed to β-amyloid plaque deposition and TAU protein hyperphosphorylation and aggregation, leading to neuronal death. Concurrently, similar cannabinoids to the ones derived from Cannabis sativa are present in the endocannabinoid system, acting through receptors CB1R and CB2R and other related receptors such as Trpv-1 and GPR-55, and are being extensively investigated for AD therapy. Given the limited efficacy and adverse effects of current available treatments, alternative approaches are crucial. Therefore, this review aims to identify effective natural and synthetic cannabinoids and elucidate their beneficial actions for AD treatment. PubMed and Scopus databases were queried (2014–2024) using keywords such as "Alzheimer's disease" and "cannabinoids". The majority of natural (THC, CBD, AEA, etc.) and synthetic (JWH-133, WIN55,212-2, CP55-940, etc.) cannabinoids included, showed promise in improving memory, cognition, and behavioral symptoms, potentially via pathways involving antioxidant effects of selective CB1R agonists (such as the BDNF/TrkB/Akt pathway) and immunomodulatory effects of selective CB2R agonists (TLR4/NF-κB p65 pathway). Combining anticholinesterase properties with cannabinoid moiety may enhance therapeutic responses, addressing cholinergic deficits of AD brains. Thus, the positive outcomes of the majority of studies discussed supports further advancing cannabinoids in clinical trials for AD treatment.
... enzima Caspase impedindo assim que as células neuronais sofram morte celular programada. E tem a capacidade de proteger os neurônios contra a toxicidade induzida por oligômeros de beta-amiloide(ASO & FERRER, 2014;CAO et al., 2014;SINGH et al., 2019).O CBD atua nos receptores GPR55 e GPR12(STROOPER & KARRAN, 2016;ALLENDE et al., 2020). Tanto o CBD quanto Δ 9 -THC individualmente, ou em combinação (CBD+Δ 9 -THC), demonstraram reduzir a astrogliose e microgliose. ...
Alzheimer's Disease is a progressive neurodegenerative condition that results in cognitive decline and behavioral changes. This article aims to analyze the therapeutic potential of phytocannabinoids in Alzheimer's Disease. We conducted a systematic search of articles published from 2014 to May 2024 in the MEDLINE (PubMed), LILACS, and SCOPUS databases, using terms related to Alzheimer's Disease, neuroinflammation, endocannabinoid system, phytocannabinoids, cannabis, cannabinoid, cannabidiol, and delta-9-tetrahydrocannabinol. The results of this systematic review provide a comprehensive overview of the interaction between neurodegeneration and the endocannabinoid system, highlighting the potential of phytocannabinoids as therapeutic interventions for Alzheimer's Disease.
... In vitro studies with non-selective agonists of CB 1 R and CB 2 R reveal that both ∆ 9 -THC and ∆ 8 -THC reduce Aβ aggregation and improve cell viability, with ∆ 9 -THC also diminishing GSK-3β and TAU levels [73]. ∆ 8 -THC was further shown to upregulate proteasome subunits and ubiquitin, suppress the unfolded protein response, reduce Bax, and increase Bcl-2 levels [74]. ...
Alzheimer’s disease (AD), a progressive neurodegenerative disorder, manifests through dysregulation of brain function and subsequent loss of bodily control, attributed to β-amyloid plaque deposition and TAU protein hyperphosphorylation and aggregation, leading to neuronal death. Concurrently, similar cannabinoids to the ones derived from Cannabis sativa are present in the endocannabinoid system, acting through receptors CB1R and CB2R and other related receptors such as Trpv-1 and GPR-55, and are being extensively investigated for AD therapy. Given the limited efficacy and adverse effects of current available treatments, alternative approaches are crucial. Therefore, this review aims to identify effective natural and synthetic cannabinoids and elucidate their beneficial actions for AD treatment. PubMed and Scopus databases were queried (2014–2024) using keywords such as “Alzheimer’s disease” and “cannabinoids”. The majority of natural (Δ9-THC, CBD, AEA, etc.) and synthetic (JWH-133, WIN55,212-2, CP55-940, etc.) cannabinoids included showed promise in improving memory, cognition, and behavioral symptoms, potentially via pathways involving antioxidant effects of selective CB1R agonists (such as the BDNF/TrkB/Akt pathway) and immunomodulatory effects of selective CB2R agonists (TLR4/NF-κB p65 pathway). Combining anticholinesterase properties with a cannabinoid moiety may enhance therapeutic responses, addressing cholinergic deficits of AD brains. Thus, the positive outcomes of the vast majority of studies discussed support further advancing cannabinoids in clinical trials for AD treatment.
Cannabinoids (the endocannabinoids, the synthetic cannabinoids, and the phytocannabinoids) are well known for their various pharmacological properties, including neuroprotective and anti-inflammatory features, which are fundamentally important for the treatment of neurodegenerative diseases. The aging of the global population is causing an increase in these diseases that require the development of effective drugs to be even more urgent. Taking into account the unavailability of effective drugs for neurodegenerative diseases, it seems appropriate to consider the role of cannabinoids in the treatment of these diseases. To our knowledge, few reviews are devoted to cannabinoids’ impact on modulating central and peripheral immunity in neurodegenerative diseases. The objective of this review is to provide the best possible information about the cannabinoid receptors and immuno-modulation features, peripheral immune modulation by cannabinoids, cannabinoid-based therapies for the treatment of neurological disorders, and the future development prospects of making cannabinoids versatile tools in the pursuit of effective drugs.
Objective: To evaluate the therapeutic potential of Cannabis sp extract in a model of Alzheimer's disease induced by aluminum chloride in rats. Methods: Thirty Wistar rats were divided into five groups (n=6) where one group received no treatment, another group received only aluminum chloride and the others, in addition to aluminum chloride, received different doses (50, 100 and 150µl) of oily extract of Cannabis sp. The animals were euthanized one day after treatment, where the brain was collected, fixed, processed and embedded in paraffin. Histological sections of the hippocampus were used for qualitative and quantitative assessment of morphological changes. Blood serum was also obtained to determine indicators of oxidative status. Results: Reduction of more than 80% in cell death in the dentate gyrus region of the hippocampus in animals treated with cannabis extract. Furthermore, a reduction in total protein levels by approximately 20% and an increase (15%) in antioxidant enzymes in relation to the positive control were also observed in the serum. Conclusion: The use of the oily extract of Cannabis sp. in a 2:1 ratio of delta-9-tetrahydrocannabinol (THC): Cannabidiol (CBD) effectively reduced hippocampal neuron deaths from amyloidosis induced in chronic aluminum chloride intoxication.
Background: There is an urgent need for novel therapies to treat Alzheimer's disease. Among others, the use of cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) has been proposed as a putative approach based on their anti-inflammatory effects. Methods: The present work was designed to explore the effects of chronic (28 days) treatment with low doses of cannabinoids: CBD (0.273 mg/kg), THC (0.205 mg/kg) or a combination of both (CBD:THC; 0.273 mg/kg:0.205 mg/kg) in the 5xFAD mouse model of AD. Results: Our data revealed that THC-treated 5xFAD mice (but not other treatment groups) exhibited anxiogenic and depressant-like behavior. A significant improvement in spatial memory was observed only in the CBD:THC-treated group. Interestingly, all cannabinoid-treated groups showed significantly increased cortical levels of the insoluble form of beta amyloid 1-42. These effects were not accompanied by changes in molecular parameters of inflammation at the mRNA or protein level. Conclusions: These data reveal differential effects of chronic, low-dose cannabinoids and point to a role of these cannabinoids in the processing of amyloid peptides in the brains of 5xFAD mice.
Leading neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by the impairment of memory and motor functions, respectively. Despite several breakthroughs, there exists a lack of disease‐modifying treatment strategies for these diseases, as the available drugs provide symptomatic relief and bring along side effects. Bioactive compounds are reported to bear neuroprotective properties with minimal toxicity, however, a detailed elucidation of their modes of neuroprotection is lacking. The review elucidates the neuroprotective mechanism(s) of some of the major phyto‐compounds in pre‐clinical and clinical studies of AD and PD to understand their potential in combating these diseases. Curcumin, eugenol, resveratrol, baicalein, sesamol and so on have proved efficient in countering the pathological hallmarks of AD and PD. Curcumin, resveratrol, caffeine and so on have reached the clinical phases of these diseases, while aromadendrin, delphinidin, cyanidin and xanthohumol are yet to be extensively explored in pre‐clinical phases. The review highlights the need for extensive investigation of these compounds in the clinical stages of these diseases so as to utilize their disease‐modifying abilities in the real field of treatment. Moreover, poor pharmacokinetic properties of natural compounds are constraints to their therapeutic yields and this review suggests a plausible contribution of nanotechnology in overcoming these limitations.
Alzheimer's disease is associated with increased production and aggregation of amyloid-β (Aβ) peptides. Aβ peptides are derived from the amyloid precursor protein (APP) by sequential proteolysis, catalysed by the aspartyl protease BACE, followed by presenilin-dependent γ-secretase cleavage. Presenilin interacts with nicastrin, APH-1 and PEN-2 (ref. 6), all of which are required for γ-secretase function. Presenilins also interact with α-catenin, β-catenin and glycogen synthase kinase-3β (GSK-3β), but a functional role for these proteins in γ-secretase activity has not been established. Here we show that therapeutic concentrations of lithium, a GSK-3 inhibitor, block the production of Aβ peptides by interfering with APP cleavage at the γ-secretase step, but do not inhibit Notch processing. Importantly, lithium also blocks the accumulation of Aβ peptides in the brains of mice that overproduce APP. The target of lithium in this setting is GSK-3α, which is required for maximal processing of APP. Since GSK-3 also phosphorylates tau protein, the principal component of neurofibrillary tangles, inhibition of GSK-3α offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles, two pathological hallmarks of Alzheimer's disease.
Although both human epidemiologic and animal model studies have suggested that caffeine/coffee protects against Alzheimer's disease, direct human evidence for this premise has been lacking. In the present case-control study, two separate cohorts consisting of 124 total individuals (65-88 years old) were cognitively assessed and a blood sample taken for caffeine/biomarker analysis. Subjects were then monitored for cognitive status over the ensuing 2-4 year period to determine the extent to which initial plasma caffeine/biomarkers levels would be predictive of changes in cognitive status. Plasma caffeine levels at study onset were substantially lower (-51%) in mild cognitive impairment (MCI) subjects who later progressed to dementia (MCI→DEM) compared to levels in stable MCI subjects (MCI→MCI). Moreover, none of the MCI→DEM subjects had initial blood caffeine levels that were above a critical level of 1200 ng/ml, while half of stable MCI→MCI subjects had blood caffeine levels higher than that critical level. Thus, plasma caffeine levels greater than 1200 ng/ml (≈6 μM) in MCI subjects were associated with no conversion to dementia during the ensuing 2-4 year follow-up period. Among the 11 cytokines measured in plasma, three of them (GCSF, IL-10, and IL-6) were decreased in MCI→DEM subjects, but not in stable MCI→MCI subjects with high plasma caffeine levels. Coffee would appear to be the major or perhaps only source of caffeine for such stable MCI patients. This case-control study provides the first direct evidence that caffeine/coffee intake is associated with a reduced risk of dementia or delayed onset, particularly for those who already have MCI.
Alzheimer's disease is rapidly growing worldwide and yet there is no cure for it. Currently available drugs only provide symptomatic relief and do not intervene in disease process sufficiently enough to prevent or cure it. Characteristic features of this disease are decline in neuronal mass and cognitive functions. The most dominant hypothesis proposed for pathogenesis of this disease is called "amyloid hypothesis". It states that excessive production of amyloid peptides called abeta peptides (Aβ) is the underlying cause of neuronal death and dysfunction. However, recent drugs designed based on amyloid hypothesis have failed in clinical trails, demanding fresh assessment. Early and persistent molecular events in this disease progression are energy deficiency and high oxidative stress in the neurons. Our review will put together a disease model based on known human and animal data with regards to breakdown in neuronal energy generation. The model will integrate energy deficits as the cause of neuronal dysfunction and abeta peptide production culminating in catastrophic loss of cognitive functions. Finally, based on this model, we will also suggest enzyme targets in neuronal bioenergetics pathway for design and development of new disease modifying therapies.
Alzheimer's disease (AD) is reaching epidemic proportions, yet a cure is not yet available. While the genetic causes of the rare familial inherited forms of AD are understood, the causes of the sporadic forms of the disease are not. Histopathologically, these two forms of AD are indistinguishable: they are characterized by amyloid-β (Aβ) peptide-containing amyloid plaques and tau-containing neurofibrillary tangles. In this review we compare AD to frontotemporal dementia (FTD), a subset of which is characterized by tau deposition in the absence of overt plaques. A host of transgenic animal AD models have been established through the expression of human proteins with pathogenic mutations previously identified in familial AD and FTD. Determining how these mutant proteins cause disease in vivo should contribute to an understanding of the causes of the more frequent sporadic forms. We discuss the insight transgenic animal models have provided into Aβ and tau toxicity, also with regards to mitochondrial function and the crucial role tau plays in mediating Aβ toxicity. We also discuss the role of miRNAs in mediating the toxic effects of the Aβ peptide.
Microglial activation is an invariant feature of Alzheimer's disease (AD). It is noteworthy that cannabinoids are neuroprotective by preventing β-amyloid (Aβ)-induced microglial activation both in vitro and in vivo. On the other hand, the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms. In the present study, we compared the effects of CBD with those of other cannabinoids on microglial cell functions in vitro and on learning behavior and cytokine expression after Aβ intraventricular administration to mice. CBD, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone [WIN 55,212-2 (WIN)], a mixed CB(1)/CB(2) agonist, and 1,1-dimethylbutyl-1-deoxy-Δ(9)-tetrahydrocannabinol [JWH-133 (JWH)], a CB(2)-selective agonist, concentration-dependently decreased ATP-induced (400 μM) increase in intracellular calcium ([Ca(2+)](i)) in cultured N13 microglial cells and in rat primary microglia. In contrast, 4-[4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl]-6,6-dimethyl-bicyclo[3.1.1]hept-2-ene-2-methanol [HU-308 (HU)], another CB(2) agonist, was without effect. Cannabinoid and adenosine A(2A) receptors may be involved in the CBD action. CBD- and WIN-promoted primary microglia migration was blocked by CB(1) and/or CB(2) antagonists. JWH and HU-induced migration was blocked by a CB(2) antagonist only. All of the cannabinoids decreased lipopolysaccharide-induced nitrite generation, which was insensitive to cannabinoid antagonism. Finally, both CBD and WIN, after subchronic administration for 3 weeks, were able to prevent learning of a spatial navigation task and cytokine gene expression in β-amyloid-injected mice. In summary, CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD. Given that CBD lacks psychoactivity, it may represent a novel therapeutic approach for this neurological disease.
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.
Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed serine/threonine kinase that plays a key role in the pathogenesis of Alzheimer's disease (AD). GSK3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in paired helical filaments, and GSK3 activity contributes both to amyloid-β production and amyloid-β-mediated neuronal death. Thus, mice generated in our laboratory with conditional overexpression of GSK3 in forebrain neurons (Tet/GSK3β mice) recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, and reactive astrocytosis, as well as spatial learning deficit. In this review, we describe recent contributions of our group showing that transgene shutdown in that animal model leads to normal GSK3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, thus further supporting the potential of GSK3 inhibitors for AD therapeutics. In addition, we have combined transgenic mice overexpressing the enzyme GSK3β with transgenic mice expressing tau with a triple FTDP-17 mutation that develop prefibrillar tau-aggregates. Our data suggest that progression of the tauopathy can be prevented by administration of lithium when the first signs of neuropathology appear. Further, it is possible to partially reverse tau pathology in advanced stages of the disease, although the presence of already assembled neurofibrillary tangle-like structures cannot be reversed.
Background:
Paired helical filaments (PHFs) are a characteristic pathological feature of Alzheimer's disease; their principal component is the microtubule-associated protein tau. The tau in PHFs (PHF-tau) is hyperphosphorylated, but the cellular mechanisms responsible for this hyperphosphorylation have yet to be elucidated. A number of kinases, including mitogen-activated protein (MAP) kinase, glycogen synthase kinase (GSK)-3 alpha, GSK-3 beta and cyclin-dependent kinase-5, phosphorylate recombinant tau in vitro so that it resembles PHF-tau as judged by its reactivity with a panel of antibodies capable of discriminating between normal tau and PHF-tau, and by a reduced electrophoretic mobility that is characteristic of PHF-tau. To determine whether MAP kinase, GSK-3 alpha and GSK-3 beta can also induce Alzheimer's disease-like phosphorylation of tau in mammalian cells, we studied the phosphorylation status of tau in primary neuronal cultures and transfected COS cells following changes in the activities of MAP kinase and GSK-3.
Results:
Activating MAP kinase in cultures of primary neurons or transfected COS cells expressing tau isoforms did not increase the level of phosphorylation for any PHF-tau epitope investigated. But elevating GSK-3 activity in the COS cells by co-transfection with GSK-3 alpha or GSK-3 beta decreased the electrophoretic mobility of tau so that it resembled that of PHF-tau, and induced reactivity with eight PHF-tau-selective monoclonal antibodies.
Conclusions:
Our data indicate that GSK-3 alpha and/or GSK-3 beta, but not MAP kinase, are good candidates for generating PHF-type phosphorylation of tau in Alzheimer's disease. The involvement of other kinases in the generation of PHFs cannot, however, be eliminated. Our results suggest that aberrant regulation of GSK-3 may be a pathogenic mechanism in Alzheimer's disease.
β-Amyloid (Aβ) plaques in Alzheimer (AD) brains are surrounded by severe dendritic and axonal changes, including local spine loss, axonal swellings and distorted neurite trajectories. Whether and how plaques induce these neuropil abnormalities remains unknown. We tested the hypothesis that oligomeric assemblies of Aβ, seen in the periphery of plaques, mediate the neurodegenerative phenotype of AD by triggering activation of the enzyme GSK-3β, which in turn appears to inhibit a transcriptional program mediated by CREB. We detect increased activity of GSK-3β after exposure to oligomeric Aβ in neurons in culture, in the brain of double transgenic APP/tau mice and in AD brains. Activation of GSK-3β, even in the absence of Aβ, is sufficient to produce a phenocopy of Aβ-induced dendritic spine loss in neurons in culture, while pharmacological inhibition of GSK-3β prevents spine loss and increases expression of CREB-target genes like BDNF. Of note, in transgenic mice GSK-3β inhibition ameliorated plaque-related neuritic changes and increased CREB-mediated gene expression. Moreover, GSK-3β inhibition robustly decreased the oligomeric Aβ load in the mouse brain. All these findings support the idea that GSK3β is aberrantly activated by the presence of Aβ, and contributes, at least in part, to the neuronal anatomical derangement associated with Aβ plaques in AD brains and to Aβ pathology itself.
Mitochondrial dysfunction is a hallmark of Alzheimer's disease (AD) and is observed in mutant amyloid precursor protein (APP) transgenic mouse models of familial AD. Melatonin is a potent antioxidant, can prevent toxic aggregation of Alzheimer's beta-amyloid (Aβ) peptide and, when taken long term, can protect against cognitive deficits in APP transgenic mice. To study the effects of melatonin on brain mitochondrial function in an AD model, APP/PS1 transgenic mice were treated for 1 month with melatonin. Analysis of isolated brain mitochondria from mice indicated that melatonin treatment decreased mitochondrial Aβ levels by two- to fourfold in different brain regions. This was accompanied by a near complete restoration of mitochondrial respiratory rates, membrane potential, and ATP levels in isolated mitochondria from the hippocampus, cortex, or striatum. When isolated mitochondria from untreated young mice were given melatonin, a slight increase in respiratory rate was observed. No such effect was observed in mitochondria from aged mice. In APP-expressing neuroblastoma cells in culture, mitochondrial function was restored by melatonin or by the structurally related compounds indole-3-propionic acid or N(1)-acetyl-N(2)-formyl-5-methoxykynuramine. This restoration was partially blocked by melatonin receptor antagonists indicating melatonin receptor signaling is required for the full effect. Therefore, treatments that stimulate melatonin receptor signaling may be beneficial for restoring mitochondrial function in AD, and preservation of mitochondrial function may an important mechanism by which long term melatonin treatment delays cognitive dysfunction in AD mice.