Impact of the Cannabinoid System in Alzheimer's Disease

Abstract

Cannabinoids are compounds isolated from cannabis and are also widely present in both nervous and immune systems of animals. In recent years, with in-depth research on cannabinoids, their clinical medicinal value has been evaluated, and many exciting achievements have been continuously accumulating, especially in the field of neurodegenerative disease. Alzheimer's disease is the most common type of neurodegenerative disease that causes dementia and has become a global health problem that seriously impacts human health today. In this review, we discuss the therapeutic potential of cannabinoids for the treatment of Alzheimer’s disease. How cannabinoids act on different endocannabinoid receptor subtypes to regulate Alzheimer’s disease and the roles of the endocannabinoid system in Alzheimer’s disease are outlined, and the underlying mechanisms are discussed. Finally, we summarize the most relevant opportunities of cannabinoid pharmacology related to Alzheimer’s disease and discuss the potential usefulness of cannabinoids in the clinical treatment of Alzheimer’s disease.

1. INTRODUCTION

Neurodegenerative diseases are a group of heterogeneous diseases characterized by the progressive and selective loss of anatomically- or physiologically-related neuronal systems [1]. Alzheimer’s disease (AD) is a highly complicated neurodegenerative disease that seriously affects human health. It was first described by German neuroscientist Alois Alzheimer in a 51-year-old patient Auguste Deter, who suffered from severe memory loss. During the autopsy of this patient, plaques and tangles in the cerebral cortex were found [2]. Subsequent studies have revealed that the histopathological features of AD involve the accumulation of β-amyloid (Aβ), intracellular aggregation of neurofibrillary tangles (NFTs), loss of a specific subset of neurons, and neuroinflammation resulting from glial activation [3-5]. Aβ and NFT are considered the main causes of disease progression; therefore, amyloid and phosphorylated microtubule-related tau proteins have become important targets for AD research. The production of amyloid begins with the cleavage of amyloid precursor protein (APP) on the plasma membrane by β-secretase (BACE1) and γ-secretase to produce insoluble Aβ fibrils. Then insoluble Aβ fibrils form oligomers, diffuse into the synaptic cleft, and interfere with synaptic signaling [6-8]. In AD patients, Aβ plaques are initially found in the basal, temporal lobe, and orbitofrontal neocortex areas of the brain and later spread throughout the entire neocortex, hippocampus, amygdala, diencephalon, and basal ganglia [9, 10]. In severe cases, Aβ is also found in the midbrain, lower brainstem, and cerebellar cortex, indicating that the accumulation of Aβ plaques is positively correlated with the course of AD [9, 10]. High concentrations of Aβ cause kinases to hyper-phosphorylate and activate microtubule-associated tau proteins, causing tau proteins to aggregate into insoluble NFTs. After plaques and tangles accumulate, microglia gather around the plaques. This promotes the activation of microglia and local inflammation and aggravates neurotoxicity, eventually leading to cognitive decline [11]. Importantly, AD is associated with an early loss of synaptic proteins, and the levels and distributions of some synaptic proteins have been found to be associated with dementia severity [12].

It has long been hypothesized that Aβ exerts toxicity in brain neurons [13, 14]. Although existing evidence reveals the harmful effects of Aβ on cellular Ca²⁺ homeostasis, neurotransmission, neuronal signaling, and receptor/ion channel function [15], the precise mechanisms of Aβ toxicity are still unclear. Particularly, which targets specifically mediate Aβ toxicity are still elusive. At present, the true causes of AD are still unclear, and even though decades of research have been conducted, there is still no drug that can effectively slow down the progression and improve the learning and memory deficits in Alzheimer's disease [16, 17]. Aβ accumulation and aggregation in neuritic or senile plaques and severe, selective cholinergic neuronal deficits are characteristic hallmarks of AD [13]. The extent of learning and memory deficits in AD is proportional to the degree of forebrain cholinergic neuronal degeneration, and the extent of Aβ deposition is used to characterize disease severity [13]. Processes, such as impairment of neurotrophic support and disorders of glucose metabolism, have been implicated in cholinergic neuronal loss and AD [18]. However, neurotoxic effects of Aβ across a range of in vivo or in vitro models suggested that Aβ plays a role in cholinergic neuronal degeneration and consequent learning and memory deficits [13, 19]; however, their mechanisms are still unclear. Therefore, understanding of such mechanisms is significant to help improve AD diagnosis and treatment.

Emerging lines of evidence indicate that a high level of Aβ induces neuronal or neurocircuit hyperexcitation. For example, chronic exposure to high levels of Aβ sensitizes some neuronal networks to hyperexcitation [20]. In animals that over-express Aβ, the high levels of Aβ peptide cause epileptiform activity within the entorhinal-hippocampal circuitry [21]. Westmark et al. compared seizure threshold (test response to pentylenetetrazol, PTZ) between AD model animals (Tg2576) and wild-type mice, and found a reduction in seizure threshold in AD model animals [22]. These shreds of evidence suggest that Aβ induces neuronal hyperexcitation, and reduction of this hyperexcitation may play a role in preventing/improving the pathogenesis of AD and could also open new therapeutic avenues. The cannabinoid system may perfectly fix this problem.

Thus far, there are 2 types of US FDA-approved drugs for the treatment of AD based on acetylcholinesterase inhibitors (donepezil, galantamine, and rivastigmine) [23] and NMDA receptor antagonists (memantine) [24]. All of these drugs are only symptomatic treatments, and none can prevent or delay the progression of AD, let alone cure AD [25], and unfortunately, promising preclinical results have repeatedly failed to be translated into clinical applications [26]. Although Aduhelm (aducanumab) has been approved recently by the FDA, its efficacy is still questionable [27].

Cannabis, as a controversial drug, has become increasingly prominent in the AD research field [28-30]. In the late 20^th century, the first cannabis-derived compound was approved for clinical use, and subsequently, it was approved for treating neurological disorders [31-34]. For example, the approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid, cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and purified botanical cannabidiol for the treatment of otherwise untreatable forms of pediatric epilepsy have suggested a potential for clinical use of cannabinoids and endocannabinoids in neurological diseases [33]. Low concentrations of Δ9-tetrahydrocannabinol (THC) can reduce the Aβ level of N2a-variant amyloid-β protein precursor (APP) cells and inhibit Aβ aggregation by directly interacting with Aβ peptide [35]. THC attenuates Aβ accumulation in the human CNS cell line (MC65 cells) in a model whereby an inducible Aβ protein exerts toxicity through an inflammatory response [36]. In addition, THC can competitively inhibit enzyme acetylcholinesterase (AChE) by binding to its peripheral anion sites, thereby increasing ACh levels and reducing Aβ-peptide aggregation induced by AChE [37]. Furthermore, it was found that pretreatment with cannabidiol (CBD) can inhibit the expression of proteins involved in tau phosphorylation and Aβ production in gingival mesenchymal stem cells [38]. Therefore, it is suggested that cannabis can be used as a novel potential drug for the treatment of AD. In this review, we summarize recent discoveries and developments of cannabinoids and analyze the data of cannabinoids that regulate AD through the activation of cannabinoid receptor type 1 (CB1) receptors, cannabinoid receptor type 2 (CB2) receptors, and the endocannabinoid system.

2. CANNABIS, CB1, AND CB2 RECEPTORS

The earliest use of cannabis as a drug can be traced back to around 2350 BC [39]. Cannabis contains a variety of compounds. The main components of cannabinoids are cannabidiol (CBD) and THC, both of which are lipophilic metabolites of resorcinol [40]. CBD was isolated in the late 1930s, but it was not until 1963 that the structure was defined [41] and identified as the active substance in hashish [42].

With in-depth studies on THC, the cannabinoid type 1 receptor (CB1R) was discovered in 1988 [43], and then the endogenous cannabinoid N-arachidonoyl-ethanolamine (AEA) was discovered in 1992 [44]. Later, a second endocannabinoid 2-arachidonic acid glyceride (2-AG) was identified [45]. These two endocannabinoids are derivatives of arachidonic acid, and they have different syntheses and metabolisms by different pathways.

Howlett was the first to report that cannabinoids may inhibit the formation of cAMP through receptors, and the efficacy of the cannabinoids examined is parallel to the level of their pharmacological effects [46]. Subsequently, the CB1R was cloned in 1990 [47]. Later, the cannabinoid type 2 receptor (CB2R) was found in the spleen in 1993 [48].

CB1R belongs to the superfamily of G protein-coupled receptors (GPCRs). The expressions of CB1Rs are distributed throughout the body in mammals, with CB1R expression highest in the basal ganglia in the central nervous system (CNS), including the substantia nigra (SNr), globus pallidus, hippocampal dentate gyrus, and the molecular layer of the cerebellum [49, 50], while the density of CB1Rs observed in the main sensory and motor areas is much lower [51, 52], suggesting that CB1Rs are involved in motivation (marginal) and cognitive (associative) information processing. Table 1 summarizes the CB1R distribution.

Table 1.

The expression trend of CB1Rs in various neurological diseases.

Brain Regions	Tendency	Species	Neurological Disorders	References
Prefrontal cortex, hippocampus, and caudate putamen	Decrease	Humans	AD	[53-55]
Dorsal hippocampus (DH), basolateral amygdala complex (BLA)	Decrease	Mice(model)	12-month-old AD	[56]
Cerebellum, dentate nucleus	Decrease	Mice(model)	Cerebellar ataxia	[57, 58]
Striatum	Decrease	Mice(model)	Huntington's disease	[59, 60]
Prefrontal and midcingulate cortex	Decrease	Humans, rat (model)	Parkinson's disease	[61-63]

Cannabinoid receptor type 2 (CB₂) is a plasma membrane G-protein-coupled receptor cloned in 1993 [64]. Since then, the expression and function of CB₂Rs in the brain have been debated. Previous studies suggested that CB₂Rs were absent in the brain since CB₂ mRNA transcripts were not detected in rat brain using in situ hybridization (ISH) [48]. Consistent with this finding, Northern blot analysis also failed to detect CB₂ mRNA in rat, mouse, and human brains [65-67]. Real-time polymerase chain reaction (RT-PCR) assays demonstrated abundant CB₂ mRNA among immune tissues, such as the spleen and on macrophages, but barely detectable levels in rat and mouse brains [65, 66, 68, 69]. Based on these findings, CB₂Rs have been classically considered ‘peripheral cannabinoid receptors’ [48, 70, 71]. Recently, this concept has been challenged by the identification of CB₂Rs throughout the central nervous system (CNS) [72-74], particularly in microglial cells [75, 76], though they are expressed at lower densities than CB₁Rs. When compared to CB₁Rs, central CB₂Rs exhibit the following unique features: (1) Lower expression levels, suggesting that these receptors may not mediate the effect of cannabis under normal physiological conditions, (2) Highly inducible, meaning that under certain pathological conditions (e.g., addiction, inflammation, stroke, schizophrenia, stress, anxiety, etc.), CB₂R expression is enhanced in the brain [77], suggesting a close relationship between the alteration of CB₂R expression/function and various psychiatric and neurological diseases, and (3) Exhibit special distribution, given that CB₂Rs are chiefly expressed in neuronal somatodendritic areas [74] (postsynaptic) but CB₁Rs are predominantly expressed on neuronal terminals, especially on GABAergic terminals (presynaptic), which leads to some opposing effects after activation by these two receptor subtypes [78]. Considering these characteristic features, the CB₂R appears to be an important substrate for neuroprotection [79], and targeting CB₂Rs will likely offer a novel therapeutic strategy for treating neuropsychiatric and neurological diseases without typical CB₁R-mediated side-effects. Given these positive implications, an urgent need to understand the functional effects of CB₂Rs in the brain, especially in the mesocorticolimbic system, has emerged within the scientific community.

Emerging evidence shows that significant CB₂ mRNA has been detected by ISH in cultured granule cells among the granule layer and Purkinje cell layer of the mouse cerebellum [80], in mouse retina [81], and the globus pallidus of non-human primates [82]. RT-PCR analysis has also been used to detect CB₂ mRNA expression in various brain regions, including the retina [81], cortex [82-85], striatum [66, 85], hippocampus [82], amygdala [84, 85], brainstem [72], and cerebellum [86]. Furthermore, two CB₂ mRNA transcripts (CB_2A and CB_2B) have been identified in the rodent and human brain [83], along with a new CB₂ transcript that has been found in mouse and human B lymphocytes [87]. Moreover, immunoblot and IHC assays have detected significant CB₂-like bands or immunostaining in various brain regions [72, 73, 88-90]. This suggests a possibility that CB₂R expression not only exists in peripheral tissues but also in the brain. As mentioned previously, CB₂Rs mediate a variety of important modulations in DA-associated behaviors [91], including food intake, body weight [92-95], depression [96], anxiety [84, 97], and schizophrenia-like behavior [85, 98]. Recent reports emerging from several labs, including ours, have shown that brain CB₂Rs play a pivotal role in the elimination of cocaine, alcohol, and nicotine addiction [99-101]. Collectively, these lines of evidence strongly suggest an important impact of CB₂Rs on the mesocorticolimbic system as well as critical roles in various brain functions, including psychiatric, cognitive, and neurobiological activity. Table 2 summarizes CB2R distribution.

Table 2.

The expression trend of CB2Rs in various neurological diseases.

Brain Regions	Tendency	Species	Neurological Disorders	References
Hippocampus and entorhinal and parahippocampal cortices	Increase	Humans and mice (model)	AD	[34, 55, 102]
Granular layer, Purkinje cells	Increase	Humans	Spinocerebellar ataxias	[103, 104]
Striatal microglia	Increase	Humans and mice (model)	Huntington's disease	[105, 106]
Substantia nigra microglial cells, striatal	Increase	Humans, rat (model) and mice (model)	Parkinson's disease	[107-109]
Spinal cord microglia	Increase	Mice (model)	Amyotrophic lateral sclerosis	[110]

It has been shown that CB2Rs play an important role in neural precursor cell proliferation, axonal guidance, and synaptic transmission [111, 112]. As a G protein-coupled receptor, signal transduction initiated by the CB2R is mediated by Gi/o [113], increasing intracellular calcium levels by activating the phospholipase C (PLC) and inositol 1,4,5-trisphosphate (IP3) signaling pathways [114]. CB2Rs inhibit cAMP, thereby reducing intracellular cAMP levels [115]. In addition, CB2R activation can also be combined with other cellular pathways, including PKA, ERK1/2, and P38 [116, 117]. In contrast to CB1Rs, CB2R expression in the brain is relatively low, but it is highly inducible under pathological conditions, suggesting that CB2Rs are related to many neurological diseases [77, 118], and CB2Rs are mainly expressed in the postsynaptic soma dendritic region, so the activation of CB2Rs has an important protective effect on neurons [118, 119].

3. EFFECTS OF CB1RS ON AD PATHOGENESIS AND THERAPEUTICS

Cognitive deficits are a significant feature in AD patients, and the brain areas related to learning and cognition are rich in CB1Rs [51, 52]. Analysis of brain tissue samples from AD patients showed that the density of CB1Rs in the brains of AD patients is reduced, especially in the frontal cortex [54, 55]. Correlation analysis of neuropathological studies showed that the CB1R level of cortical brain tissue after death in AD patients is found to be lower than that of the age-matched controls [55]. In experimental animal models, reduction of CB1R expression lowers the PSD-95 protein level and aggravates learning and memory dysfunction in APP/PS1 transgenic mice, indicating that CB1Rs protect against AD-related pathological events and play a key role in AD progression [120]. In the triple transgenic mouse model of AD (3xTg-AD), CB1R activity is up-regulated in the anterior part of the thalamus at 4 months of age, while its activity in the basal nucleus of Meynert decreases at 15 months of age [121]. This is consistent with the different degrees of nitrification of CBRs in the late course of AD [54].

It has been reported that treatment with Δ9-THC significantly reduces Aβ plaques in APP transgenic mice, which may be due to the activation of the neutrophil (an Aβ-degrading enzyme) [30]. It has been found that WIN-55,212-2 (CB1R agonist) can rescue AD-like pathological features and learning deficits caused by intracerebroventricular injection of Aβ25–35 in rats [54]. In addition, another study reported that the endocannabinoid receptor system (ECBS) activates peroxisome proliferator-activated γ receptor (PPAR-γ) by activating CB1Rs, which, in turn, stimulate the expression of lipoprotein receptor protein 1 (LRP1) that has been shown to play an important role in the brain-blood transport of Aβ [122] to increase the clearance of Aβ across the blood-brain barrier [123]. It has also been reported that CB1R deficiency can aggravate AD-related cognitive deficits in AD animal models; CB1R-deficient mice showed a decrease in the number of APP plaques and its fragments [124]. However, compared to APP23 mice with intact CB1Rs, APP23/CB1^(-/-) mice exhibited learning and memory impairment.

Bilateral injection of Aβ in the prefrontal cortex will cause a significant change in the activity-dependent electrophysiological response of hippocampal CA1 pyramidal neurons. It was reported that the combination therapy with ACEA (a selective CB1R agonist) almost completely prevented the effects of Aβ treatment alone [125]. Whole-cell patch-clamp recordings showed that in the absence of synaptic input, the intrinsic action potential (AP) frequency was reduced, and the discharge irregularity increased in the Aβ treatment group. Aβ treatment also induced significant changes in spontaneous and evoked neuronal responses. However, co-treatment with ACEA enabled almost complete retention of the normal intrinsic electrophysiological properties of pyramidal cells [125]. ACEA was also found to reduce the cytotoxic effects of Aβ42 oligomers in primary cultures of cortical neurons and reverse the Aβ-induced glycogen synthase kinase-3β (GSK3β) dephosphorylation in vitro and in vivo [126]. Moreover, compared with age-matched vehicle-treated APP transgenic mice, ACEA-treated mice showed a reduced astrocytic response near Aβ plaques and decreased expression of the proinflammatory cytokine interferon-γ in astrocytes. ACEA is present in both the neurons, which mediate at least in part by GSK3β inhibition, and the glia, resulting in decreased reactive astrocytes and reduced interferon-γ expression [126, 127]. Therefore, with the progression of AD, the expression of CB1R gradually decreases, and early CB1R activation can reduce the deposition of Aβ plaques, decrease neurotoxicity, and rescue learning and memory deficits. This suggests that targeted activation of CB1Rs might provide a novel approach to treat AD.

4. EFFECTS OF CB2RS ON AD PATHOGENESIS AND THERAPEUTICS

Changes in the expression of ECB receptors during the pathogenesis of AD may be time-dependent. In this regard, CB1 and CB2 have different expression patterns. CB1Rs in the hippocampus and frontal lobe show higher levels of activity in the early stages of AD, but their activity decreases as the disease progresses [104, 128]. In contrast, in the late stage of AD, the expression of CB2Rs is found to be higher when neuroinflammation is more pronounced, and microglia and astrocytes are activated [128].

The upregulation of CB2R and its preferential distribution near Aβ plaques have been reported in several AD animal models and postmortem studies, suggesting that CB2R expression is induced in the course of AD [54, 55, 102]. Activation of these receptors stimulates the removal of amyloid by macrophages [129]. It has been reported that activation of CB2R up-regulates PPARγ signaling and attenuates Aβ-induced neuroinflammation, neurodegeneration, and spatial memory impairment in animals [130]. It was found that CB2R agonist JWH-133 reduced Thr181 tau phosphorylation, as well as the expression of GSK3β, p38, and the active form of SAPK/JNK in APP/PS1 mice [131], and also reduced the levels of superoxide dismutase (SOD) 1 and 2 in APP/PS1 mice [132]. Treating AD mice with 1-phenylisatin (a selective modulator of CB2R) can prevent streptozotocin and aluminum trichloride + d-galactose-induced learning and memory impairment and brain damage [133]. Long-term oral administration of two different cannabinoid agonists (WIN 55,212-2 and JWH-133) was found to rescue neuroinflammation, reduce Aβ levels, and improve the cognitive ability of Tg APP 2576 mice [134]. Activating CB2Rs with a lower dose of JWH-015 could remove natural Aβ from human tissue sections and stimulate the human THP-1 macrophage cell line, but not U373MG astrocytoma cells, to endocytose synthetic pathogenic Aβ peptides bound to a culture dish, and this effect was reversed by the selective CB2R antagonist SR144528 [129]. In addition, lack of CB2Rs failed to change tau phosphorylation in mice [135]. In J20APP mice, the lack of CB2Rs reduced total tau without exerting any effects on tau phosphorylation [136]. These results suggested that activation of CB2Rs can reduce tau phosphorylation and help the clearance of Aβ plaques.

In addition, studies have shown that the enhanced coupling of cannabinoid receptor/effector levels in the hippocampus and frontal cortex of mice decreases significantly with age [137], which may be related to the nitrosylation of receptors, which may cause damage to the connection between the receptor and its effectors during the course of AD [54]. This is consistent with a study that found that the availability of CB2Rs in AD patients is reduced compared to healthy individuals [138].

In the APP/PS1 AD mouse model, loss of CB2Rs reduces the activation of microglia and the infiltration of macrophages. In addition, these mice express low levels of pro-inflammatory chemokines and cytokines in the brain, as well as reduced concentrations of soluble Aβ 40/42 [139]. It has been reported that CB2R activation converts microglia from the M1 to M2 phenotype [140] and facilitates phagocytosis [141]. In addition, a new type of CB2R agonist (MDA7) provides protection against Aβ fibril-induced activation of microglia and astrocytes, normalizes CB2R expression, promotes Aβ clearance, weakens synaptic plasticity defects, and impairs learning and memory [142]. In an in vitro experiment, selective CB2 agonists prevented the Aβ-induced release of pro-inflammatory cytokines by reducing intracellular calcium concentration and enhancing microglia phagocytosis [143]. The activation of CB2Rs by JWH-015 increases Aβ-induced astrocyte proliferation in cell culture [144]. It has been shown that administration of the CB2R agonist JWH-133 prevented the activation of microglia and the release of pro-inflammatory cytokines near Aβ deposits in APP transgenic mice [132]. In addition, Aβ-induced CD40-mediated phagocytosis of microglia was found to be inhibited by the CB2R agonist JWH-015 [145]. A specific role for CB2Rs in the modulation of tau is suggested by the potentiation of autophagy and improvement in the redox state. Recently, we have shown that in a hippocampal culture cell model, JWH-133 significantly prevented chronic Aβ-induced neuronal toxicity [146], supporting the idea that CB2Rs possess a neuroprotective effect against chronic Aβ-induced neuronal degeneration.

5. EFFECTS OF ENDOCANNABINOIDS ON AD PATHOGENESIS AND THERAPEUTICS

Two primary endocannabinoids in brain tissue (anandamide and 2-arachidonylglycerol) have been identified as CB1R and CB2R agonists [44, 147, 148]. The neuroprotective effects of endocannabinoids may be due to interference with several cellular and molecular mechanisms, including apoptosis and inflammation [149, 150]. The progression of AD is related to the changes in the endocannabinoid system [151, 152]. Both cannabinoid receptor agonists and endocannabinoids, such as AEA, can reduce the neurotoxicity caused by Aβ-peptide in a mitogen-activated protein kinase (MAPK) pathway in a dependent manner by activating CB1Rs to protect human NTERA-2/cl-D1 teratocarcinoma cells [153].

Studies have reported that 8-month-old Aβ APPswe/ PS1ΔE9 mice have lower 2-AG levels than wild-type mice in the striatum [137]. 2-AG treatment can prevent Aβ-induced hemichannel activity and inflammatory characteristics in astrocytes and neuronal damage caused by excitotoxic glutamate release in hippocampal slices treated with Aβ [154]. Furthermore, early administration of 2-AG reuptake inhibitor (VDM11) can prevent hippocampal damage and memory loss in rats [155]. Increasing 2-AG by inhibiting MAGL can prevent APP/PS1 prostaglandin (PGE2) production in mice, as well as neuroinflammation-related Aβ42 accumulation and neurodegeneration [156]. Inhibition of MAGL can also reduce the expression of the β-amyloid precursor protein lyase 1 (BACE1) in AD mouse models, inhibit the production and accumulation of Aβ, maintain the integrity of hippocampal synaptic structure and function, and improve long-term synaptic plasticity, spatial learning, and memory, as well as inhibit the activation of microglia and astrocytes to prevent neuroinflammation and reduce neurodegeneration [157].

AEA has been reported to up-regulate Notch-1 signaling in cultured neurons. Regulating Notch signaling has recently emerged as a possible approach for altered neurogenesis [158]. Exposing cultured neurons to Aβ (1-42) will increase the endogenous Notch-1 inhibitor numb (Nb) expression, leading to impaired Notch-1 signaling. Adding AEA can prevent Nb expression and enhance Notch-1 signaling [159]. The stimulating effect of AEA on Notch-1 signaling persists in the presence of Aβ (1-42). Through Notch-1 signaling, AEA may be able to help restore neurogenesis and cognition in AD [159].

6. EFFECTS OF THC AND CBD ON AD PATHOGENESIS AND THERAPEUTICS

Current treatments of AD mainly target symptoms, and there are no therapeutics available in clinical practice to prevent the neurodegenerative progress or induce neuronal repair. The increased lines of evidence demonstrate that the delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) cannabinoids of the plant Cannabis sativa have shown neuroprotection in AD animal models [160, 161].

In general, cannabis smoking is a reversible disruption of short-term memory induced by THC, the primary psychoactive component of cannabis. However, a recent report showed that THC is also able to improve neurological function in old animals when chronically administered at low concentrations [162]. For example, a recent study reported that an N2a-variant of amyloid β precursor (APP) cells treated with low doses of THC showed a neuroprotective effect on the cells. The possible targets for THC include decreased Aβ levels in tested cells. THC directly interacts with the Aβ peptide, thereby inhibiting aggregation. Moreover, it inhibits the enzyme acetylcholinesterase, enhances the mitochondria function, and reduces glycogen synthase kinase-3β (GSK-3β) and related signaling pathways [35]. These data sets strongly suggest that THC could be a potential therapeutic option for AD through multiple functions and pathways. Furthermore, recent studies have demonstrated that THC paradoxically promotes hippocampal neurogenesis, prevents neurodegenerative processes occurring in animal models of Alzheimer's disease, protects from inflammation-induced cognitive damage, and restores memory and cognitive function in old mice [163-165]. However, in the study, the THC was administered only twice for 48 h; thus, this may not be sufficient to establish a conclusion. Further studies are needed to determine the dose-dependency and time-dependency of potential treatment of cannabinoids to exert a continuous neuroprotective effect and understand the subsequent ceasing of neurodegeneration and neuronal repair [161].

Cannabidiol (CBD) is one of the most well-known phytocannabinoid used in the treatment of AD. In general, it presents low toxicity and poor systemic absorption via oral administration of capsules or aqueous emulsions by humans and animals [163]. The studies have demonstrated the ability of CBD to reduce reactive gliosis and neuroinflammatory responses [166] as well as promote neurogenesis [167]. Importantly, CBD was also found to reverse and prevent the development of cognitive deficits in AD rodent models [168]. Although the pharmacological mechanisms of CBD-induced neuroprotection are still not well known, it has been suggested that CBD exhibits antioxidant, anti-inflammatory properties, and moderate brain region-specific reductions in insoluble Aβ40 levels [169]. Furthermore, CBD was shown to protect against Aβ-mediated neurotoxicity and microglial-activated neurotoxicity [170] to reduce Aβ production by inducing APP ubiquitination [170] and improve cell viability [171]. These features suggest that CBD is perfectly used to prevent and treat pathogenic processes typically found in AD.

7. LIMITATION OF BRAIN ECBS AS A THERAPEUTIC TARGET

The main challenges in the use of cannabinoids in the treatment of AD come from the following aspects. First, there are no obvious molecular markers in the diagnosis of AD disease, and timely treatment cannot be carried out [172, 173]. Secondly, the distribution of the ECBS in terms of time and space is difficult to control, which increases treatment difficulty [174]. For example, CB2Rs have great potential for treating AD, but the expression of CB2Rs in the central nervous system is relatively low; however, its expression is high in the periphery, and it is highly inducible [118]. Therefore, when and how to specifically target CB2Rs becomes a major challenge. Finally, endocannabinoids are naturally present in mammals, but so far, there is no specific agonist/antagonist regimen to avoid unwanted health outcomes to treat AD [175].

CONCLUSION

The ECBS, as a potential therapeutic target for AD, mainly involves the regulation of excitability mediated through CB1R and CB2Rs and is based on cannabinoids targeting several important processes involved in the pathogenesis of AD, such as beta-amyloid protein deposition and tau protein phosphorylation, inflammation, mitochondrial dysfunction, and excitatory neurotoxicity (Fig. 1).

Fig. (1).

CB2R-mediated neuroprotection.

LIST OF ABBREVIATIONS

AD

Alzheimer’s Disease

APP

Amyloid Precursor Protein

CNS

Central Nervous System

ECBS

Endocannabinoid Receptor System

LRP1

Lipoprotein Receptor Protein 1

NFTs

Neurofibrillary Tangles

SOD

Superoxide Dismutase

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

This work was supported by the Key Area Research and Development Program of Guangdong Province (2018B030334001), the 2020 Li Ka Shing Foundation Cross-Disciplinary Research Grant (2020LKSFG01A), and CNSF (81771437).

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.