The authors of a recent paper have reviewed the literature regarding the potential of cannabinoids to treat Alzheimer’s disease [1].
The endocannabinoid system and Alzheimer’s disease
Aging is a well-known risk factor for Alzheimer’s, and more than 50% of people over 85 are expected to suffer from it [2]. There is a need to find an effective Alzheimer’s therapy, since currently used treatments only address its symptoms.
The research found that the endocannabinoid system (ECS) is dysregulated in Alzheimer’s [3]. Review authors speculate that restoring the levels of endocannabinoids and ECS receptor activity can be a potential avenue to prevent Alzheimer’s progression.
ECS has several components, including the cannabinoid 1 receptor (CB1R), the cannabinoid 2 receptor (CB2R), endocannabinoids, and their transport and metabolism proteins. CBRs are naturally activated by endocannabinoids, which include eicosanoids, such as 2-AG and anandamide/AEA.
Aging is associated with changes to ECS. Human and animal studies reported reduced expression of CB1R and ECR-related metabolites in different brain regions [4].
Analyzing postmortem brain tissues from Alzheimer’s patients revealed overexpression of CB2R in glial cells that surround the senile plaques. Additionally, one of the proteins that take part in the AEA metabolism, namely, fatty acid amino hydrolase (FAAH) that converts AEA into inflammatory pathway precursor, arachidonic acid, is increased in reactive astrocytes that surround neuritic plaques. On the other hand, CB1R expression was found to be downregulated in the tissues of the frontal cortex [5].
Since phytocannabinoids, compounds extracted from the plant Cannabis sativa, modulate ECS, the authors suggest that they could potentially be used as therapeutics for Alzheimer’s. Several metabolites of Cannabis sativa interact with the components of ECS signaling. Two major ones are cannabidol (CBD), the major non-psychotropic component, and Δ9-tetrahydrocannabinol (Δ9THC), the major psychotropic component. Both have an affinity for CB1R and CB2R. However, cannabinol (CBN), cannabigerol (CBG), cannabidivarin (CBDV), and cannabichromene (CBC) are also important players.
Cannabinoids as Alzheimer’s therapeutics
The review’s authors address different aspects of Alzheimer’s and discuss research that has shown that those aspects can be remedied by cannabinoid treatment. First, they address neuroinflammation, as Alzheimer’s patients often chronically experience this. Non-clinical evidence shows that phytocannabinoids can modulate neuroinflammation by their impact on ECS.
Investigation in mouse cell cultures has shown that phytocannabinoids can suppress cytokine production and influence T cell function. In human cell cultures, CBD has shown promise in potentially repairing the blood-brain barrier, which can be disrupted in Alzheimer’s [6, 7].
Similar results were obtained in vivo. Research done in rodents inoculated with amyloid beta has shown that CBD led to a reduction in cytokines and pro-inflammatory mediators. Similar results were obtained with synthetic cannabinoids [8, 9].
The next aspect of Alzheimer’s discussed in the paper is neurotrophic factor signaling. Neurotrophic factors are molecules that regulate synaptic plasticity and neurogenesis and prevent neuroinflammation and neuronal death. Neurotrophic factors include such molecules as TGF-1, BDNF, and Insulin-like growth factor 1 (IGF1).
Research in healthy subjects has shown that acute administration of Δ9THC led to increased BDNF levels. However, chronic exposure to Δ9THC leads to CB1R downregulation and reduces BDNF release [10].
In the early stages of Alzheimer’s, IGF1 levels are increased. Δ9THC and CBD may potentially decrease elevated IGF1 levels; however, this experiment was conducted on a Huntington’s disease model [11].
Effects on plaques
Amyloid beta plaques are one of the main characteristics of Alzheimer’s. Therefore, preventing their accumulation is often a main goal of treatment.
Research in cell cultures has shown that CBD can inhibit amyloid beta-induced tau protein hyperphosphorylation and decrease amyloid beta production [12, 13]. Δ9THC shows similar properties, and it potentially inhibits amyloid beta synthesis and may prevent amyloid beta aggregation [14].
In vitro studies in a human neuron-like cell line suggest that other phytocannabinoids, specifically CBDV, CBG, CBC, CBN, and CBD, can remove already formed and aggregated amyloid beta and stimulate their degradation [15].
When a combination of Δ9THC and CBD was used in mice, there were lower levels of the most toxic soluble amyloid beta form and a reduction of amyloid beta oligomers and tau pathology. Synthetic cannabinoids, when administered in rats, also showed accelerated amyloid beta clearance [16, 17, 18].
Dendritic spine density and morphology was the next main area of focus in this review. Dendritic spines are small protrusions from dendrites. They form contacts with axons of neighboring neurons. During aging, the researchers observed reduced spine volume and length along with lower density of dendritic spines [19, 20].
The authors note the scarcity of research on dendritic spines and cannabinoids. In their review, they noted that evidence from cell cultures and mouse models points to the neuroprotective effects of both synthetic cannabinoids and phytocannabinoids. Cannabinoids have been found to reduce neuronal death and cell gaps and to enable neurogenesis [21, 22, 23].
There were also memory and cognitive tests on mice with amyloid beta-induced deficits. The reviewers noted a reversal in spatial memory and learning deficits along with improvements in social recognition memory and novel object recognition [24, 25, 26].
Pleiotropic effects of cannabinoids and their therapeutic potential
The authors emphasize that there are not many studies on cannabinoids being used as Alzheimer’s treatments. However, the existing data shows the pleiotropic effect of cannabinoids on Alzheimer’s, as it targets many mechanisms and pathways.
Despite the limited research and lack of clinical data, the authors believe that cannabinoids have high therapeutic potential, however, several obstacles will need to be addressed, such as administration routes, as oral administration has variable and low bioavailability.
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