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Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic


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The limited effectiveness of current therapies against Alzheimer's disease (AD) highlights the need for intensifying research efforts devoted to developing new agents for preventing or retarding the disease process. During the last few years, targeting the endogenous cannabinoid system has emerged as a potential therapeutic approach to treat Alzheimer. The endocannabinoid system is composed by a number of cannabinoid receptors, including the well-characterized CB1 and CB2 receptors, with their endogenous ligands and the enzymes related to the synthesis and degradation of these endocannabinoid compounds. Several findings indicate that the activation of both CB1 and CB2 receptors by natural or synthetic agonists, at non-psychoactive doses, have beneficial effects in Alzheimer experimental models by reducing the harmful β-amyloid peptide action and tau phosphorylation, as well as by promoting the brain's intrinsic repair mechanisms. Moreover, endocannabinoid signaling has been demonstrated to modulate numerous concomitant pathological processes, including neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress. The present paper summarizes the main experimental studies demonstrating the polyvalent properties of cannabinoid compounds for the treatment of AD, which together encourage progress toward a clinical trial.
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published: 05 March 2014
doi: 10.3389/fphar.2014.00037
Cannabinoids for treatment of Alzheimers disease: moving
toward the clinic
Ester Aso1,2 * and Isidre Ferrer1,2 *
1Institut de Neuropatologia, Servei d’Anatomia Patològica, Institut d’Investigació Biomèdica de Bellvitge-Hospital Universitari de Bellvitge,
Universitat de Barcelona, L’Hospitalet de Llobregat, Spain
2Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Spain
Edited by:
Cesare Mancuso, Catholic University
School of Medicine, Italy
Reviewed by:
Mauro Maccarrone, Campus
Bio-Medico University of Rome, Italy
Antonio Calignano, University of
Naples Federico II, Italy
Ester Aso and Isidre Ferrer, Institut de
Neuropatologia, Servei d’Anatomia
Patològica, Institut d’Investigació
Biomèdica de Bellvitge-Hospital
Universitari de Bellvitge, Universitat
de Barcelona, Carrer Feixa Llarga s/n,
08907 L’Hospitalet de Llobregat,
The limited effectiveness of current therapies against Alzheimer’s disease (AD) highlights
the need for intensifying research efforts devoted to developing new agents for preventing
or retarding the disease process. During the last few years, targeting the endogenous
cannabinoid system has emerged as a potential therapeutic approach to treat Alzheimer.
The endocannabinoid system is composed by a number of cannabinoid receptors,
including the well-characterized CB1and CB2receptors, with their endogenous ligands
and the enzymes related to the synthesis and degradation of these endocannabinoid
compounds. Several findings indicate that the activation of both CB1and CB2receptors
by natural or synthetic agonists, at non-psychoactive doses, have beneficial effects in
Alzheimer experimental models by reducing the harmful β-amyloid peptide action and tau
phosphorylation, as well as by promoting the brain’s intrinsic repair mechanisms. Moreover,
endocannabinoid signaling has been demonstrated to modulate numerous concomitant
pathological processes, including neuroinflammation, excitotoxicity, mitochondrial dysfunc-
tion, and oxidative stress. The present paper summarizes the main experimental studies
demonstrating the polyvalent properties of cannabinoid compounds for the treatment of
AD, which together encourage progress toward a clinical trial.
Keywords: cannabinoids, Alzheimer, CB1receptor, CB2receptor, β-amyloid, tau, oxidative stress, neuro-
Alzheimer is an age-dependent neurodegenerative process dis-
tinct from normal aging and characterized morphologically by
the presence of senile plaques, mainly composed of different
species of fibrillar β-amyloid (Aβ) produced by the cleavage
of the Aβprecursor protein (APP) due to β- and γ-secretases,
and by the presence of neurofibrillary tangles, mostly composed
of various isoforms of hyper-phosphorylated and nitrated tau
protein (Duyckaerts and Dickson, 2011;Ferrer, 2012). One ten-
dency of opinion proposes that Aβtriggers plaque formation, tau
hyper-phosphorylation, and disease progression (Hardy, 2009).
This may happens in a percentage of familial Alzheimer’s dis-
ease (AD) cases linked to mutations in genes encoding APP,
and presenilin 1 and presenilin 2 which are enzymes involved
in the cleavage of APP, or in Down syndrome (Bertram and
Tanzi, 2011). However, tau hyper-phosphorylation precedes Aβ
deposition in many cerebral regions in sporadic cases of AD
(Braak and Braak, 1999).
Recent studies have shown that Aβacts as a seed of new Aβpro-
duction and deposition under appropriate conditions (Frost and
Diamond, 2010) and that abnormal tau promotes the production
and deposition of hyper-phosphorylated tau under determinate
experimental conditions (Clavaguera et al., 2009). Therefore, Aβ
and hyper-phosphorylated tau promote the progression of the
pathological process in an exponential way once these abnormal
proteins are accumulated in the brain (Goedert et al., 2010;Ferrer,
In addition to these pathological hallmarks, multiple alter-
ations converge in the pathogenesis of AD, including genetic
and environmental factors. Vascular factors and concomitant
pathologies worsen disease symptoms (Kovacs et al., 2008). Mito-
chondrial functional defects, increased production of reactive
oxygen and nitrogen species (ROS and RNS), and damage to
enzymes involved in energy metabolism are causative of nerve
cell exhaustion (Pamplona et al., 2005;Ferrer, 2009;Sultana and
Butterfield, 2010).
Altered lipid composition of membranes particularly lipid rafts
(Martín et al., 2010), inflammatory responses (Akiyama et al.,
2000), and altered production of trophic factors, neurotransmitter
and neuromodulators, together with impaired function of degra-
dation pathways such as those related to cytoplasmic proteolysis,
autophagy, and ubiquitin–proteasome system play crucial roles as
well (Keller et al., 2000;Ferrer, 2012;Selkoe, 2012).
Neurofibrillary tangles first appear in middle age in selected
nuclei of the brain stem, later in the entorhinal cortex, and
then extend to other parts of the brain (Braak and Braak,
1999;Simic et al., 2009). Senile plaques appear first in the
orbitofrontal and temporal cortex and then extend to the
whole cortex, diencephalic nuclei, and eventually to the cere-
bellum at terminal stages (Braak and Braak, 1999). Synaptic
loss, reduced dendritic arbors, progressive isolation of remain-
ing neurons and nerve cell loss occurs with disease progression,
and affects multiple brain regions not only the cerebral cor-
tex but also the amygdala, nuclei of the forebrain including March 2014 |Volume 5 |Article 37 |1
Aso and Ferrer Cannabinoids in Alzheimer
Meynert nucleus, striatum, thalamus, and selected nuclei of
the brain stem thus involving multiple neurotransmitter systems
(Duyckaerts and Dickson, 2011).
Importantly, the progression from early stages of the neu-
rodegenerative process to symptomatic stages may take decades,
whereas once the cognitive impairment and dementia appear the
disease progression is much more rapid. Therefore,Alzheimer is a
relatively well-tolerated degenerative process during a long period
of time, but it may have devastating effects once thresholds are
crossed (Ferrer, 2012). These facts highlight the need to search
for treatments that act on selective targets during the silent period
of the disease, aimed at curbing or retarding disease progression
toward dementia (Ferrer, 2012;Selkoe, 2012).
During the last few years, targeting the endogenous cannabi-
noid system (ECS) has emerged as a potential therapeutic
approach to treat Alzheimer in such first stages. Endocannabi-
noid signaling has been demonstrated to modulate the main
pathological processes occurring during the silent period of the
neurodegenerative process, including protein misfolding, neu-
roinflammation, excitotoxicity, mitochondrial dysfunction, and
oxidative stress. The present paper summarizes the experimental
studies demonstrating the multi-faceted properties of cannabinoid
compounds for the treatment of AD.
The last two decades of research have brought a tremendous
improvement in knowledge of the endocannabinoid system com-
ponents and functions under physiological and pathological
conditions. This neuromodulatory system consists of cannabinoid
receptors, endogenous ligands, and several enzymes responsible
for their synthesis and degradation (Piomelli, 2003). To date, two
subtypes of cannabinoid Gi/o-coupled receptors, CB1and CB2,
have been fully characterized and cloned. However, cannabinoid
compounds may also bind to other receptors, such as GPR55, per-
oxisome proliferator-activated receptors PPARαand PPARγ, and
transient receptor potential vannilloid-1 (TRPV1) channels (Mac-
carrone et al., 2010;Pertwee et al., 2010). CB1receptors are the
most abundant G protein-coupled receptors in the central neural
system, expressed in both neurons and glial cells, where they regu-
late important brain functions including cognition and memory,
emotion, motor control, feeding, and pain perception (Wilson and
Nicoll, 2002;Howlett, 2005). CB1receptors are mostly located at
the terminals of neurons of the central and peripheral nervous
system where they act as modulators of excitatory and inhibitory
neurotransmission. Moreover, CB1receptors are also found in
peripheral tissues, playing an important role in energy balance
and metabolism (Silvestri and Di Marzo, 2013). CB2receptors are
localized in cells of the immune system and modulate the immune
cell migration and the release of cytokines; within the nervous
system CB2receptors are mainly located in microglia (Cabral and
Griffin-Thomas, 2009). Relatively low CB2receptor expression
has also recently been identified in some neurons (Van Sickle et al.,
2005;Brusco et al., 2008;Onaivi et al., 2008). Further evidence
of CB2receptor expression in neurons comes from the observa-
tion that axonal damage in one cerebellar hemisphere induced
the expression of CB2receptors in contralateral precerebellar neu-
rons; CB2receptor agonist facilitated neuronal survival, whereas
the selective PI3K inhibitor blocked CB2R effects on axotomized
neurons (Viscomi et al., 2009). Most of the knowledge acquired
about cannabinoid receptor pharmacology was made possible
by the study of the mechanisms of action of numerous natural,
but also synthetic, cannabinoid compounds. Among the natural
cannabinoids, the most well-known are 9-tetrahydrocannabinol
(9-THC), the main psychoactive compound of the Cannabis
sativa plant, and cannabidiol (CBD), which is devoid of any psy-
choactivity, both differing in cannabinoid receptor affinity and
activity (Pertwee, 2008).
The characterization of CB1and CB2receptors permitted
the discovered of endocannabinoids or cannabinoids produced
and released by nerve cells. Endocannabinoids are lipid com-
pounds of the eicosanoid family derived from the degradation
of membrane phospholipids (Piomelli, 2003). The most repre-
sentative are arachidonoylethanolamine (AEA), also named anan-
damide, and 2-arachidonoylglycerol (2-AG),although several oth-
ers have also been identified, such as 2-arachidonylglyceryl ether
(2-AGE), virodhamine, and N-arachidonyldopamine (Piomelli,
2003). Endocannabinoids act as neurotransmitters since they are
synthesized and released by neurons, are able to bind and acti-
vate membrane receptors, and are inactivated by reuptake and
enzymatic degradation within the cell. However, endocannabi-
noids have two fundamental characteristics that differentiate them
from other neurotransmitters: they act as retrograde messen-
gers and they do not accumulate in the interior of synaptic
vesicles (Wilson and Nicoll, 2002). For several years, endo-
cannabinoid compounds have been supposed to be exclusively
synthesized on demand to act on cells located near their site
of synthesis, and then to be rapidly inactivated by the action
of specific degradation enzymes. However, recent studies have
shown intracellular stores of anandamide in places other than
synaptic vesicles as in adiposomes where it is sequestered and
concentrated to higher levels than in the extracellular space
(Hillard and Jarrahian, 2000;Maccarrone et al., 2010). More-
over, an active intracellular binding of anandamide to TRPV1
and PPARs suggest an additional role of anandamide as a sec-
ond messenger in intracellular signaling (Maccarrone et al., 2010).
This new scenario contemplates the possibility that anandamide
may act as an autocrine/paracrine ligand of CB receptors but
also as an intracellular ligand to TRPV1 and PPARs; more-
over, the presence of extracellular anandamide transporters would
point anandamide as an endocrine messenger (Maccarrone et al.,
Interestingly, neuronal damage can increase the production
of endocannabinoids, which may provide a defense mechanism
against toxicity (Stella et al., 1997;Marsicano et al., 2003). In
the case of AEA, the synthesis is performed from the phos-
phatidylethanolamine existing in the cell membrane by the
successive action of 2 enzymes, the N-acetyltransferase and phos-
pholipase D (PLD). AEA action is determined by two processes
that limit their availability, (i) transport from the synaptic cleft
into the cell by passive diffusion or by a selective transporter,
and (ii) the hydrolysis caused by two enzyme systems, mainly
the fatty acid amide hydrolase (FAAH) but also monoacylglycerol
lipase (MAGL; Di Marzo etal., 1994). 2-AG is the most abun-
dant endogenous cannabinoid in the brain and its concentration
Frontiers in Pharmacology |Experimental Pharmacology and Drug Discovery March 2014 |Volume 5 |Article 37 |2
Aso and Ferrer Cannabinoids in Alzheimer
is about 200 times that of AEA (Stella et al., 1997). The forma-
tion of 2-AG is mediated by phospholipase C and diacylglycerol
lipase (DAGL),and also produced on demand. In contrast to AEA,
MAGL seems to be more involved in 2-AG degradation than FAAH
(Dinh et al., 2002).
Interest in the role that ECS may play in neurodegenerative
processes is based on findings revealing that the augmentation
of cannabinoid tone contributes to brain homeostasis and neu-
ron survival, suggesting that may offer protection against the
deleterious consequences of pathogenic molecules.
The analysis of human post-mortem samples revealed some alter-
ations in ECS composition and signaling in AD brains, although
the bestowal of such modifications in the pathophysiology of the
disease remains to be elucidated. The modifications described
for CB1receptors in AD are ambiguous. Whereas some authors
have reported a significant reduction in the CB1levels in cor-
tical areas and in neurons distant from senile plaques (Ramírez
et al., 2005;Solas et al., 2013), others have described no changes
in the expression, distribution, or availability of CB1recep-
tors in cortex and hippocampus in AD (Benito et al., 2003;Lee
et al., 2010;Mulder et al., 2011;Ahmad et al., 2013)orhave
failed to dissociate CB1receptor expression changes from normal
aging (Westlake et al., 1994). No correlation between CB1lev-
els and any AD molecular marker or cognitive status has been
found (Solas et al., 2013). In contrast, there is no controversy
regarding the significant increase of CB2levels in AD brains,
mainly corresponding to receptors expressed on microglia sur-
rounding senile plaques (Ramírez et al., 2005;Solas et al., 2013).
Interestingly, expression levels of CB2receptors correlates with
Aβ42 levels and plaque deposition, although not with cogni-
tive status (Solas et al., 2013), suggesting that such pathogenic
events induce CB2receptor expression. Additionally, both CB1
and CB2cannabinoid receptors in the AD brain are nitro-
sylated, and this could contribute to the impaired coupling
of these receptors to downstream effector signaling molecules
(Ramírez et al., 2005).
A few studies addressed other components of ECS in AD
human samples. The first study analyzing endocannabinoid levels
reported no differences between AD patients and healthy con-
trols in the plasmatic concentrations of AEA and 2-AG (Koppel
et al., 2009). However, a recent lipidomic study in post-mortem
brain samples revealed lower AEA levels in midfrontal and tempo-
ral cortices in AD compared to control subjects, which inversely
correlated with the neurotoxic brain Aβ42 peptide levels and
cognitive deficiencies recorded in these patients, suggesting a
contribution for Aβ42-dependent AEA impairment to cognitive
dysfunction (Jung et al., 2012). Moreover, some alterations have
been found in the contents and/or activity of the enzymes related
to endocannabinoid synthesis and degradation in AD brains.
Thus, the endocannabinoid metabolizing enzyme FAAH is up-
regulated in AD both neuritic plaque-associated glia (Benito et al.,
2003) and in peripheral blood mononuclear cells (D’Addario
et al., 2012), and this could participate in the increase of AEA
degradation in the vicinity of the senile plaque. Such FAAH
overexpression may have at least two harmful consequences in
disease progression, (i) neuronal AEA availability limitation and
(ii) increase of pro-inflammatory molecules induced by AEA
metabolites such as arachidonic acid (Calder, 2005). An elegant
study revealed altered 2-AG signaling during late stages of AD
due to the combination of impaired MAGL recruitment and
increased DAGL levels, which subsidize synapse silencing in AD
(Mulder et al., 2011). The same study failed to detect changes
in PLD, FAAH, or TRPV1 protein levels in total hippocampal
Most of the evidence accumulated sustaining the potential thera-
peutic utility of cannabinoids in AD has been obtained by using
cellular and animal models that mimic a variety of AD-related
changes, and they will be discussed later on in this review. How-
ever,it is of note that the scarce clinical data available also support
the beneficial effects of cannabinoid compounds for treating some
behavioral symptoms related to AD. Only a few clinical trials
and one case report are available on the topic so far. In all the
cases an analog of 9-THC (nabilone or dronabinol) was tested.
Interestingly, one clinical trial including 15 AD patients resulted
in a decreased severity of altered behavior and an increase in
the body weight in AD patients, who were previously refusing
food, after 6 weeks of dronabinol treatment. Side effects associ-
ated with cannabinoid administration were limited to euphoria,
somnolence, and tiredness, but these did not warrant discontinu-
ation of therapy (Volicer et al., 1997). Similarly, two pilot studies
including eight patients with dementia concluded with a reduc-
tion in night-time agitation and behavioral disturbances, without
adverse effects during the trial period with dronabinol (Walther
et al., 2006,2011). In line with these observations, the use of the
cannabinoid receptor agonist nabilone correlated with prompt and
dramatic improvements in the severe agitation and aggressiveness
exhibited by an advanced AD patient who was refractory to anti-
psychotic and anxiolytic medications (Passmore, 2008). In spite of
the low number of patients included in these trials and the fact that
none of them evaluated cognitive or neurodegenerative markers,
the positive behavioral results are promising and represent valu-
able, albeit limited, information, considering that no remarkable
side effects were reported. However, the revision in 2009 of the
Cochrane Dementia and Cognitive Improvement Group Special-
ized Register found no evidences of cannabinoid effectiveness in
the improvement of behavior and other parameters of demen-
tia, and suggested that more controlled trials are needed to assess
the effectiveness of cannabinoids in the treatment of dementia
(Krishnan et al., 2009).
Several in vitro and in vivo studies demonstrate that certain
cannabinoid compounds confer neuroprotection against Aβ,as
previously reported elsewhere (Ruiz-Valdepeñas et al., 2010).
Some endocannabinoids such as AEA, 2-AG, and noladin ether,
directly supplied to the cell culture or augmenting their availability
through administration of endocannabinoid reuptake inhibitors,
increased the viability of neurons after exposure to different
toxic Aβspecies (Milton, 2002;Chen et al., 2011;Harvey et al., March 2014 |Volume 5 |Article 37 |3
Aso and Ferrer Cannabinoids in Alzheimer
2012;Janefjord et al., 2013), and reduced Aβ-induced memory
impairment in rats (van der Stelt et al., 2006). Similar posi-
tive results in the survival of neuronal cultures exposed to Aβ
peptide were obtained with exogenous cannabinoids such as
CBD (Iuvone et al., 2004;Janefjord et al., 2013), the selective
CB1receptor agonist arachidonyl-2-chloroethylamide (ACEA;Aso
et al., 2012), the CB2selective agonists JWH-015 and JWH-133,
and the mixed CB1/CB2receptor agonists 9-THC, HU-210,
and WIN55,212-2 (Ramírez et al., 2005;Janefjord et al., 2013).
The neuroprotective properties of exogenous cannabinoids have
consistently been demonstrated to prevent memory deficits in
Aβ-injected rats and mice for both synthetic CB1(Haghani et al.,
2012) and CB2selective agonists (Wu et al., 2013), as well as mixed
CB1/CB2receptor agonists (Ramírez et al., 2005;Martín-Moreno
et al., 2011;Fakhfouri et al., 2012) and natural CBD (Martín-
Moreno et al., 2011). Moreover, chronic treatment with ACEA
(Aso et al., 2012), JWH-133 (Martín-Moreno et al., 2012;Aso et al.,
2013), or WIN55,212-2 (Martín-Moreno et al., 2012) resulted
in cognitive improvement in two different transgenic mouse
models of brain amyloidosis. The efficacy of the cannabinoid
compounds in curbing the cognitive impairment was inversely
proportional to the disease progression stage at the beginning
of the treatment in the transgenic animals (Aso et al., 2012,
The mechanisms of action that underlie the cannabinoid neu-
roprotection against Aβ, which ultimately may lead to the memory
improvement, are multiple and are assumed to act in parallel or
interacting within them. Although most of these proposed pro-
tective mechanisms are related to the capacity of cannabinoids to
indirectly mitigate the harmful effects of Aβ, as we will discuss in
later sections of this review (i.e., inflammation, oxidative stress,
excitotoxicity, aberrant cellular signaling), some authors also
described direct effects of cannabinoids on Aβprocessing. Thus,
stimulation of CB2receptors produced Aβremoval by human
macrophages (Tolón et al., 2009;Wu et al., 2013) and favored
Aβtransport through the choroid plexus (Martín-Moreno et al.,
2012). This facilitation of Aβclearance across the blood–brain
barrier (BBB) was also demonstrated for the endocannabinoid 2-
AG, a synthetic CB1/CB2receptor agonist and MAGL inhibitors,
but no FAAH, in in vitro an in vivo BBB models (Bachmeier et al.,
2013). These findings could explain the reduction in Aβlevels and
plaque burden observed in AD mouse models chronically treated
with CB2or CB1/CB2receptor agonists (Martín-Moreno et al.,
2012) and MAGL inhibitors (Chen et al., 2012;Piro et al., 2012).
In contrast, no significant contribution of CB1receptors in Aβ
production, aggregation or clearance was reported after chronic
treatment with ACEA (Aso et al., 2012) or HU-210 (Chen et al.,
2010) in two different transgenic AD models. However, there is
a study reporting a regulatory influence of CB1receptor on APP
processing since APP23 transgenic mice deficient for CB1receptor
exhibited reduced APP protein levels and Aβplaque deposition,
likely due to changes in intracellular APP transport, although
the animals presented enhanced cognitive deficits (Stumm et al.,
2013). Moreover, a recent publication revealed that 9-THC sig-
nificantly increased the expression of neprilysin, an important
endopeptidase for Aβdegradation, but not β-site APP cleaving
enzyme 1 (BACE1), leading to a remarkable reduction of Aβ
plaques in 5xFAD APP transgenic mice (Chen et al., 2013). This
study failed, however, to clarify the specific role of CB1or CB2
receptorsinsuch9-THC effect on Aβclearance.
A role for cannabinoids in another AD pathological hallmark,
tau hyper-phosphorylation, has also been described. First stud-
ies performed in cell cultures demonstrated that CBD, ACEA,
and WIN55,212-2 inhibited tau protein hyper-phosphorylation
in Aβ-stimulated PC12 neuronal cells (Esposito et al., 2006a,b).
In the case of CBD, the effect was mediated through the reduc-
tion of the phosphorylated active form of glycogen synthase
kinase 3β(GSK-3β), one of the known tau kinases (Ferrer et al.,
2005), which in turn resulted in Wnt/β-catenin pathway rescue
and consequent reduction of neuronal apoptosis (Esposito et al.,
2006a). In contrast, the ACEA and WIN55,212-2 effect on tau
hyper-phosphorylation was selectively mediated by CB1receptor
through the down-regulation of inducible nitric oxide synthase
(iNOS) protein expression and nitric oxide (NO) production in
Aβ-stimulated astroglioma cells co-cultured with the PC12 neu-
ronal cells (Esposito et al., 2006b). In line with the described role
for CB1receptor on tau hyper-phosphorylation, chronic treat-
ment with the CB1selective agonist ACEA reduced the levels of
tau phosphorylated at Thr181 site in the area surrounding Aβ
plaques in treated APP/PS1 mice, probably through the ACEA-
induced reduction in GSK-3βharmful activity (Aso et al., 2012).
Moreover, a specific role for CB2receptor in the modulation of tau
phosphorylation was also suggested. Chronic JWH-133 adminis-
tration reduced tau hyper-phosphorylation in the vicinity of Aβ
plaques in APP/PS1 mice, which may be explained by decreased
activity of GSK-3β, p38, and stress-activated protein kinase/c-Jun
NH(2)-terminal kinase (SAPK/JNK) kinases in the treated animals
(Aso et al., 2013).
Confirming these observations, a recent study reported a
marked reduction in neurofibrillary tangles in parkin-null, human
tau overexpressing (PK//TauVLW) mice, a model of complex
frontotemporal dementia, parkinsonism, and lower motor neuron
disease, after prolonged exposure to Sativex®, an already approved
medicine based on mixed 9-THC and CBD natural extracts
(Casarejos et al., 2013). The authors suggested the cannabinoid
potentiation of autophagy or improvement of redox state as likely
mechanisms accounting for the reduction in tau deposition.
Neuroinflammation, initially manifested as microglial activation,
is a prominent feature in AD which contributes to progressive
cell damage and neuron loss (Akiyama et al., 2000;Hensley, 2010;
Sardi et al., 2011). As CB2receptors are essentially expressed in
the immune system including microglial cells, where they are
known to inhibit microglia-mediated neurotoxicity, the main
interest in the role of cannabinoids as anti-inflammatory agents
in several diseases concurring with inflammation has focused
on compounds acting on CB2receptors (Cabral and Griffin-
Thomas, 2009). In the case of AD, several studies reported
that activation of CB2receptors reduced the neuroinflammatory
response to Aβinsults in different models of the disease. After
the inoculation of Aβinto the rat or mouse brain, selective or
Frontiers in Pharmacology |Experimental Pharmacology and Drug Discovery March 2014 |Volume 5 |Article 37 |4
Aso and Ferrer Cannabinoids in Alzheimer
mixed CB2receptor agonists reduced microglial response and
pro-inflammatory molecule production in a plethora of stud-
ies (Ramírez et al., 2005;van der Stelt et al., 2006;Esposito
et al., 2007;Fakhfouri et al., 2012;Wu et al., 2013). Similarly,
selective CB2receptor agonists decreased the number of acti-
vated microglial cells surrounding Aβdeposition and the levels
of pro-inflammatory cytokines in at least two APP transgenic
models (Martín-Moreno et al., 2012;Aso et al., 2013). Moreover,
the 9-THC and CBD natural mixture present in Sativex®also
blunted the microglial reactivity in a genetic tauopathy model
(Casarejos et al., 2013), although no evidence of direct impli-
cation of CB2receptors or other receptors in such effects was
provided. In fact, other mechanisms related to ECS components
distinct from CB2receptors could explain the anti-inflammatory
effects of the Sativex®preparation. As noted above, 9-THC
is a partial agonist of CB1receptors, which could also play a
role in the AD inflammatory process according to a recent study
demonstrating that chronic treatment with the selective agonist
ACEA reduced the astrocytic expression of the pro-inflammatory
cytokine interferon-γin APP/PS1 transgenic mice (Aso et al.,
2012). Additionally, CBD, which has no affinity for CB1or
CB2receptors, also presents anti-inflammatory properties in AD
models (Esposito et al., 2006a;Martín-Moreno et al., 2011). The
precise site at which CBD could exert its neuroinflammatory and
neuroprotective effects is still not fully elucidated, but some find-
ings point to the selective involvement of PPARγin such CBD
properties (Esposito et al., 2011).
The enzymes related to AEA and 2-AG degradation also con-
tribute to modulating the inflammatory process in AD models.
FAAH is expressed in both neurons and astrocytes, where it may
play a role in the response to inflammation. In fact, an astrocyte-
specific increase in FAAH expression is markedly maintained in
neuroinflammatory conditions including amyloidosis, which was
assumed to contribute to the harmful processes induced by toxic
insults because of the reduction in endocannabinoid tone (Ben-
ito et al., 2003). However, cortical mouse astrocytes genetically
modified to lack FAAH exhibited a pro-inflammatory phenotype
when exposed to Aβ, characterized by an increase in cytokine
concentration and cell death probably due to the modification
of signaling cascades involved in cell survival and inflamma-
tion, such as extracellular signal-regulated protein kinases 1 and
2 (ERK1/2), p38 mitogen-activated protein kinase (p38MAPK),
and nuclear factor kappa-light-chain-enhancer of activated B
cells (NF-κB), as well as to the increase in inflammatory medi-
ators such as iNOS and cyclooxygenase (COX-2; Benito et al.,
2012). The authors demonstrated that these processes involved
PPAR-α,PPAR-γ, and TRPV1, but not CB1or CB2receptors.
Yet, the pharmacological blockade of FAAH in cell cultures did
not lead astrocytes to a pro-inflammatory phenotype, indicat-
ing that the observed effects in astrocytes lacking FAAH could
be due to compensatory changes that result from the poten-
tially prolonged enhancement of N-acylethanolamines. These
data suggest that an excessively prolonged enhancement of the
endocannabinoid tone may have harmful consequences. In con-
trast, the genetic inactivation of MAGL, an enzyme known to
hydrolyze endocannabinoids and generate the primary arachi-
donic acid pool for neuroinflammatory prostaglandins (Nomura
et al., 2011), attenuated neuroinflammation and lowered Aβlevels
and plaques in APP/PS1 mice (Piro et al., 2012). These observa-
tions were confirmed by the pharmacological blockade of MAGL,
which recapitulated the cytokine-lowering effects through reduced
prostaglandin production, rather than enhanced endocannabi-
noid signaling.
Mitochondria are vital cellular components essential for ATP
production and calcium homeostasis. The relevance of these
organelles in neurons is even greater than in other cell types
because neurons are highly demanding energy cells mainly depen-
dent on aerobic oxidative phosphorylation, due to their limited
capacity for glycolysis. Long axons require energy transport
over long distances, and synaptic transmission depends on cal-
cium signals. Mitochondria are abundant in presynaptic nerve
terminals where they provide energy for sustained neurotrans-
mitter release. Therefore, defects in mitochondrial activity can
have severe consequences for the cell, including energetic fail-
ure associated with decreased ATP production and apoptosis
resulting from the release of death factors and impaired calcium-
buffering capacity. Moreover,alterations in the protein complexes
of the respiratory chain located in the inner mitochondrial
membrane lead to electron transport leakage that enables the
production of ROS, which may overwhelm the capacity of the
anti-oxidant systems existing in cells to counteract free radi-
cal damage, with the subsequent oxidative damage produced to
proteins, DNA, RNA, and lipids. Numerous studies have linked
mitochondrial dysfunction to neurodegenerative diseases, includ-
ing AD (Ferrer, 2009;Ankarcrona et al., 2010;Burchell et al.,
2010). Altered mitochondrial function appears early in time
in AD, even preceding the characteristic Alzheimer pathology
in mouse models, and ultimately leads to exhausted neurons
as a result of the convergence of reduced energy production,
increased energy demand, and excessive oxidative stress (Ferrer,
The anti-oxidant properties of cannabis derivatives, notably
CBD, were demonstrated early in cell cultures exposed to toxic
glutamate levels (Hampson et al., 1998,2000). In line with these
findings, CBD prevented ROS production and lipid peroxida-
tion in PC12 neuronal cells exposed to Aβ,aswellasreduced
apoptosis from reduced caspase 3 levels, and in counteracting
the Aβ-induced increase in intracellular calcium concentration
(Iuvone et al., 2004). CBD also reduced, in similar conditions,
the levels of nitrite (NO), a potent oxidant reactive molecule, as
well as the expression of iNOS, one of the enzymes responsible
for the synthesis of NO (Esposito et al., 2006b,2011). Moreover,
other cannabinoid compounds exhibited anti-oxidant properties
in animal models of AD. Thus, the selective CB2receptor agonist
JWH-133 reduced hydroxynonenal adducts, derived from lipid
peroxidation, and enhanced the levels of the superoxide dismu-
tases SOD1 and SOD2 in the vicinity of plaques in APP/PS1 mice,
indicating the role of CB2receptors in reducing oxidative stress
damage and to promote responses against such damage (Aso et al.,
2013). A reduction of free radicals and mitochondrial activity
was also suggested in a mouse model of tauopathy exposed to March 2014 |Volume 5 |Article 37 |5
Aso and Ferrer Cannabinoids in Alzheimer
chronic treatment with the Sativex®mixture of 9-THC and CBD
(Casarejos et al., 2013).
An additional topic deserving attention is the putative role
of cannabinoid receptors in the regulation of neuronal energy
metabolism. The little information available to date supports the
direct control of CB1over neuronal respiration and energy pro-
duction. One study, using anti-CB1receptor antibodies, revealed
CB1receptor protein localization in approximately 30% of neu-
ronal mitochondria, which when activated by exogenous or
endogenous cannabinoids reduces the respiratory chain complex I
activity and oxygen consumption, likely through cyclic adenosine
monophosphate (cAMP) and protein kinase A (PKA) signaling
(Bénard et al., 2012). These findings are in agreement with pre-
vious observations showing that AEA, 9-THC, and HU-210, all
of them partial CB1agonists, significantly decreased oxygen con-
sumption and mitochondrial membrane potential (Athanasiou
et al., 2007). However, these data must be interpreted with cau-
tion as commercial anti-CB1receptor antibodies also recognize
the mitochondrial protein stomatin-like protein 2 and that the for-
merly described effect of WIN 55,212-2 on mitochondrial complex
III is in fact not detectable in isolated mitochondrial preparations
(Morozov et al., 2013).
Nowadays the approved drugs for treating AD are based on
acetylcholine esterase (AChE) inhibitors, which increase the ACh
availability partially palliating this neurotransmitter deficiency
in AD patients, or they are non-competitive antagonists of the
N-methyl D-aspartate (NMDA) receptor, which reduce calcium
influx and limit excitotoxicity. Interestingly, certain cannabinoid
compounds act on the same targets than current medications,
resulting in similar or enhanced beneficial effects. For instance,
9-THC competitively inhibits AChE, thus increasing ACh levels,
as well as preventing AChE-induced Aβaggregation by bind-
ing in the peripheral anionic site of AChE, the critical region
involved in amyloidogenesis (Eubanks et al., 2006). The synthetic
cannabinoid HU-211 acts as a stereoselective inhibitor of NMDA
receptors, and thus protects cells from NMDA induced neu-
rotoxicity (Feigenbaum et al., 1989;Eshhar et al., 1993;Nadler
et al., 1993). In the case of HU-211, its neuroprotective activ-
ity is due to the direct binding to NMDA receptors, not to
cannabinoid receptors, but the broadly accepted cannabinoid-
mediated neuroprotection against excitotoxicity can be achieved
through a number of other different mechanisms, including inhi-
bition of presynaptic glutamate release (Marsicano et al., 2003),
blockage of voltage-dependent calcium channels (Mackie and
Hille, 1992;Tw itchell et al., 1997) and inhibition of calcium
release from ryanodine sensitive stores (Zhuang et al., 2005),
which mostly imply the direct or indirect participation of CB1
Several other mechanisms seem to contribute to the thera-
peutic properties of cannabinoid compounds in AD, although
they have not been fully characterized. Among them, we can
note the capacity of endocannabinoids to prevent Aβ-mediated
lysosomal destabilization in cultured neurons, reducing in this
way the apoptotic signaling, which in turn sustains cell sur-
vival (Noonan et al., 2010). Compromised neurogenesis is an
early event in AD that limits neuronal replacement once pro-
gressive neuronal loss takes place in the brain, contributing to
cognitive deterioration (Lazarov and Marr, 2010). Interestingly,
AEA and CBD have been described as promoting neurogene-
sis in response to Aβinsult (Esposito et al., 2011;Tanveer et al.,
2012), suggesting an additional beneficial effect of cannabinoids
in AD.
Another aspect as yet unexplored is the interaction of cannabi-
noids with neurotrophic factors in AD. Cannabinoids are capa-
ble of increasing brain-derived neurotrophic factor (BDNF;
Khaspekov et al., 2004), a neurotrophin reduced in the AD brain
(Lee et al., 2005;Peng et al., 2009), which is known to confer
protection against excitotoxicity and to promote neurogenesis
(Scharfman et al., 2005) and neuronal plasticity; all of these pro-
cesses play a role in AD. However, there is still no evidence
about the implication that such cannabinoid-induced BDNF pro-
motion could have on the cognitive or pathological aspects of
AD. Similarly, little is known about the participation of cannabi-
noid signaling in the impaired function of degradation pathways
such as autophagy and ubiquitin–proteasome, which are known
to play a relevant role in AD progression. The impairment in
these catabolic processes results in accumulation of aggregate-
prone proteins, altered mitochondria and other cellular organelles
that might exacerbate neurodegenerative process (Nixon et al.,
2005;Harris and Rubinsztein, 2011). To date, only one study has
reported beneficial effects of cannabinoid-induced autophagy in
a model of tauopathy (Casarejos et al., 2013), but this has opened
the possibility of exploring in greater detail the involvement of
ECS in promoting degradation of toxic components in neurode-
generative diseases. Finally, the effect of cannabinoids on the
regulation of cerebral blood flow may contribute to their poten-
tial benefits on AD. A number of studies have demonstrated that
certain cannabinoids produce vasodilatation of brain blood ves-
sels and increase cerebral blood flow (Ellis et al., 1995;Wagner
et al., 2001;Pacher et al., 2005;Iring et al., 2013). Consider-
ing that cerebral blood flow in AD contributes to the reduction
of oxygen and nutrients in brain (Iadecola, 2004), it can be
suggested that treatments improving cerebral perfusion such as
cannabinoids are advantageous in AD. Taken together, available
information suggest that cannabinoids may have multiple effects
on AD by acting not only as anti-oxidant and anti-inflammatory
agents, but also modulating a plethora of factors which con-
tribute to the pathogenesis of AD as altered Aβmetabolism,
autophagy, trophic factor deficiencies, and impaired blood
Considering the numerous complex pathological mechanisms
involved in the progression of AD, treatments targeting a single
causal or modifying factor offer limited benefit. Cannabinoids,
however, exhibit pleiotropic activity, targeting in parallel several
processes that play key roles in AD, including Aβand tau aber-
rant processing, neuroinflammation, excitotoxicity, mitochon-
drial dysfunction, and oxidative stress. Cannabinoids improve
behavioral disturbances, as well. These effects are summarized in
Frontiers in Pharmacology |Experimental Pharmacology and Drug Discovery March 2014 |Volume 5 |Article 37 |6
Aso and Ferrer Cannabinoids in Alzheimer
FIGURE 1 |Summary of the main findings demonstrating
beneficial effects of cannabinoid compounds in AD models.
Cannabinoids may target in parallel several processes that play key
roles in AD, including Aβand tau aberrant processing, chronic
inflammatory responses, excitotoxicity, mitochondrial dysfunction, and
oxidative stress, among others. Clinical data also reveal an
improvement in behavioral in patients with AD after treatment with
Figure 1. Then, because of these widespread properties of cannabi-
noid compounds, targeting the ECS could represent a unique and
reliable opportunity to advance toward an effective therapy against
the AD. Moreover, cannabinoids might represent a safe low-cost
therapy, with their natural origin and low side effects profile. From
our point of view, the success of cannabinoid-based therapy in
AD could be increased taking into account two important aspects:
(i) the use of a combination of compounds that cover the whole
spectrum of therapeutic properties described for cannabinoids,
i.e., combination of CB1and CB2receptors agonists plus CBD,
which presents interesting neuroprotective properties spite of its
mechanism of action remaining poorly understood, and (ii) the
early initiation of the treatment in the neurodegenerative process,
which ensures the integrity of the ECS target components and
increases the possibility of curbing the exponential degenerative
progression toward dementia.
The main concerns regarding the use of cannabis derivatives in
medicine are related with the psychoactivity of some cannabinoids,
especially 9-THC, which may disrupt short-term memory, work-
ing memory, and attention skills mainly acting through CB1
receptors, as well as with the potential 9-THC dependence
occurring after long-term use. However, the therapeutic effects of
cannabinoids must be clearly dissociated from the risks of abuse
and addiction linked to the recreational use of cannabis deriva-
tives. First, the CB1agonists with potential psychoactivity used
in experimental models to demonstrate the therapeutic properties
were administered at doses substantially lower than those produc-
ing psychoactive effects and cannabis dependence (Maldonado
et al., 2011). Second, the preferred therapeutic cannabinoid com-
bination includes CBD, which is known to mitigate the negative
consequences on cognition of 9-THC administration (Fadda
et al., 2004), and therefore insure the avoidance of such unde-
sirable effects. Finally, the brain context in healthy subjects
consuming cannabis enriched in 9-THC for recreational pur-
poses is completely different from that of AD patients subjected
to very determined combinations of cannabinoid species, in March 2014 |Volume 5 |Article 37 |7
Aso and Ferrer Cannabinoids in Alzheimer
terms of ECS organization and neuronal signaling. In conclu-
sion, in light of the polyvalent properties for the treatment of
AD and the limited side effects exhibited by these compounds,
progress toward a clinical trial to test the capacity of cannabi-
noids to curb this neurodegenerative disease seems to be fully
We thank T. Yohannan for editorial assistance. Authors’ work is
supported by Agrupació Mútua Foundation, Mutua Madrileña
Foundation, and CIBERNED (Institute of Health Carlos III,
Spanish Ministry of Economy and Competitiveness).
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Conflict of Interest Statement: The authors declare that the research was conducted
in the absence of any commercial or financial relationships that could be construed
as a potential conflict of interest.
Frontiers in Pharmacology |Experimental Pharmacology and Drug Discovery March 2014 |Volume 5 |Article 37 |10
Aso and Ferrer Cannabinoids in Alzheimer
Received: 14 January 2014; accepted: 19 February 2014; published online: 05 March
Citation: Aso E and Ferrer I (2014) Cannabinoids for treatment of Alzheimer’s disease:
moving toward the clinic. Front. Pharmacol. 5:37. doi: 10.3389/fphar.2014.00037
This article was submitted to Experimental Pharmacology and Drug Discovery, a
section of the journal Frontiers in Pharmacology.
Copyright © 2014 Aso and Ferrer. This is an open-access article distributed under the
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does not comply with these terms. March 2014 |Volume 5 |Article 37 |11
... The medical use of cannabis is gaining interest for different symptoms and diseases, including dementia and BPSD. In vitro and in vivo research suggests that cannabinoids may have neuroprotective, (Karl et al., 2012;Maroon and Bost, 2018) antioxidant, (Aso and Ferrer, 2014) immunosuppressive (Martín-Moreno et al., 2011;Karl et al., 2012), and antiinflammatory (Karl et al., 2012;Aso and Ferrer, 2014;Liu et al., 2015) properties. According to pre-clinical studies, they may also contribute to reducing the amyloid plaque formation (Aso and Ferrer, 2014;Liu et al., 2015) and the neurofibrillary degeneration (Aso and Ferrer, 2014;Liu et al., 2015). ...
... The medical use of cannabis is gaining interest for different symptoms and diseases, including dementia and BPSD. In vitro and in vivo research suggests that cannabinoids may have neuroprotective, (Karl et al., 2012;Maroon and Bost, 2018) antioxidant, (Aso and Ferrer, 2014) immunosuppressive (Martín-Moreno et al., 2011;Karl et al., 2012), and antiinflammatory (Karl et al., 2012;Aso and Ferrer, 2014;Liu et al., 2015) properties. According to pre-clinical studies, they may also contribute to reducing the amyloid plaque formation (Aso and Ferrer, 2014;Liu et al., 2015) and the neurofibrillary degeneration (Aso and Ferrer, 2014;Liu et al., 2015). ...
... In vitro and in vivo research suggests that cannabinoids may have neuroprotective, (Karl et al., 2012;Maroon and Bost, 2018) antioxidant, (Aso and Ferrer, 2014) immunosuppressive (Martín-Moreno et al., 2011;Karl et al., 2012), and antiinflammatory (Karl et al., 2012;Aso and Ferrer, 2014;Liu et al., 2015) properties. According to pre-clinical studies, they may also contribute to reducing the amyloid plaque formation (Aso and Ferrer, 2014;Liu et al., 2015) and the neurofibrillary degeneration (Aso and Ferrer, 2014;Liu et al., 2015). Some experimental and clinical studies highlight the safety of administering cannabinoids to dementia patients. ...
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Context The management of behavioral symptoms and rigidity in patients with dementia constitutes a significant challenge. Short-term studies suggest an interest in the use of medical cannabis, but long-term data are lacking. Objectives The objective of this study was to investigate the feasibility and long-term safety of administering tetrahydrocannabinol/cannabidiol (THC/CBD) treatment as an additional drug to a poly medicated population with severe dementia, evaluate clinical improvements, and collect information on the pharmacokinetics of cannabinoids and possible drug–drug interactions. Methods A prospective observational study of patients with severe dementia living in a long-term care home to whom the physicians had prescribed a medical cannabis treatment. Data were collected over 2 years. We assessed the changes in medical cannabis dosages, safety parameters, variations in neuropsychiatric problems, agitation, rigidity, the most invalidating daily activity, and disabling behavior trouble scores. We evaluated the pharmacokinetics of cannabinoids by measuring plasma levels and analyzing the enzymatic activity. Results We assessed 19 patients (81.4 years—17 women and two men) receiving an average of 12.4 mg THC/24.8 mg CBD per day for up to 13 months, with no reported problems related to the treatment and limited adverse drug reactions. Clinical scores showed a marked improvement that was stable over time, deprescription of other medications, and care facilitated. The pharmacokinetic evaluation showed an expected slight reduction in the enzymatic activity of CYP1A2 and CYP2C19. Conclusion A long-term THC/CBD (1:2) medication can be administered safely and with overall positive clinical improvement to poly medicated older adults with severe dementia and associated problems. The results must be confirmed in a randomized trial.
... The endocannabinoid system plays a fundamental role in the inhibitory control of the neuroinflammation, which represent the common mechanisms responsible for the different neurodegenerative diseases [32], including Alzheimer's and Parkinson's diseases [33][34][35][36]. Then, cannabinoids could be effective in the treatment of the neurodegenerative pathologies. ...
... Then, cannabinoids could be effective in the treatment of the neurodegenerative pathologies. Contrarily to the neoplastic diseases, for whom it is yet unclear whether the anticancer action of cannabinoids may be a dosedependent phenomenon, as well as whether the combination of cannabinoids may enhance the efficacy of the single cannabinoid agent, in the case of neurodegenerative diseases it seems that the efficacy of cannabinoids may be a dose-dependent phenomenon [33][34][35][36], and that the combination of cannabinoid may allow better therapeutic results [28]. ...
The endocannabinoid system plays a physiological natural anti-inflammatory anticancer role and the pharmacological effects of cannabinoids from Cannabis plant simply reflect the action of the endogenous ones. Therefore, from a therapeutic point of view Cannabis plant cannot be understood without taking into consideration the physio-pathological role of the endocannabinoid system. Despite the great number of potentially therapeutic molecules with the Cannabis plant, they may be synthetized within four archetypic molecules, which consist of tetra-hydro-cannabinol (THC), cannabinol (CBN), cannabigerol (CBG) and cannabidiol (CBD). All molecules play a similar anticancer activity, whereas their psychological effects are different. THC is the only psychotropic sychedelic cannabinoid, whereas the other three cannabinoids have no psychotropic effect, but exert an important anxiolytic activity. Moreover, only THC acts as a direct enzyme responsible for annabinoid degradation, by enhancing the endogenous cannabinoid content. Unfortunately, despite the great number of experimental studies, the clinical use of cannabinoids in the treatment of systemic human diseases is still at the beginning.
... CB1 ve CB2 reseptör agonisti WIN55,212-2, T hücrelerinin Th 1 efektör hücrelere farklılaşmasını azaltır, böylece infl amatuar mediatörlerin üretimini ve hastalık şiddetini azaltır (23) . CB2 reseptörü, daha belirgin bir hastalık, artan mononükleer hücre infiltrasyonu, artmış proinflamatuar sitokin üretimi (197) ile ilişkili CB2 eksikliği ile EAE ile ilişkili infl amasyonun düzenlenmesindeki rolüyle dikkate değerdir ve kordon (108) , hastalık sırasında meydana gelen nöroinfl amasyonu azaltma girişimini temsil edebilir. ...
... Dina Bosnjak Kuharic ve arkadaşları 2021 de (194) (195,196). Bununla birlikte, CB2 reseptör ekspresyonu artar ve Ab42 seviyeleri ve plak yoğunluğu ile ilişkilidir (197). Ek olarak, kannabinoidlerin hiperfosforilasyonunu inhibe ettiği (198) , asetil kolinesterazı inhibe ettiği (şu anda FDA tarafından alzheimer / demans için onaylanmış dört ilaçtan üçünün çalıştığı mekanizma) ve Ab agregasyonunu önlediği (199) gösterilmiştir. ...
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... It has been demonstrated that the endocannabinoid system (ES) plays an important role across all of these pathological stages of AD, including the promotion of intrinsic repair mechanisms and the modulation of pathological processes, including neuroinflammation. 13 However, the field currently lacks a synthesis on where it stands regarding advances in the development of ES biomarkers for AD. Herein, we comprehensively review and critically discuss the changes in the ES observed in AD and potential novel biomarker candidates. ...
Background: Alterations in the endocannabinoid system (ES) have been described in Alzheimer's disease (AD) pathophysiology. In the past years, multiple ES biomarkers have been developed, promising to advance our understanding of ES changes in AD. Discussion: ES biomarkers, including positron emission tomography with cannabinoid receptors tracers and biofluid-based endocannabinoids, are associated with AD disease progression and pathological features. Conclusion: Although not specific enough for AD diagnosis, ES biomarkers hold promise for prognosis, drug-target engagement, and a better understanding of the disease. Here, we summarize currently available ES biomarker findings and discuss their potential applications in the AD research field.
... There are several other potential beneficial aspects of cannabis for the treatment of AD that are outside the scope of this review. We direct the reader to an excellent review on the available preclinical data that support the therapeutic potential of cannabinoids in treating AD (Aso and Ferrer, 2014). ...
Full-text available
Alzheimer’s disease is a progressive neurodegenerative disorder characterized histologically in postmortem human brains by the presence of dense protein accumulations known as amyloid plaques and tau tangles. Plaques and tangles develop over decades of aberrant protein processing, post-translational modification, and misfolding throughout an individual’s lifetime. We present a foundation of evidence from the literature that suggests chronic stress is associated with increased disease severity in Alzheimer’s patient populations. Taken together with preclinical evidence that chronic stress signaling can precipitate cellular distress, we argue that chronic psychological stress renders select circuits more vulnerable to amyloid- and tau- related abnormalities. We discuss the ongoing investigation of systemic and cellular processes that maintain the integrity of protein homeostasis in health and in degenerative conditions such as Alzheimer’s disease that have revealed multiple potential therapeutic avenues. For example, the endogenous cannabinoid system traverses the central and peripheral neural systems while simultaneously exerting anti-inflammatory influence over the immune response in the brain and throughout the body. Moreover, the cannabinoid system converges on several stress-integrative neuronal circuits and critical regions of the hypothalamic-pituitary-adrenal axis, with the capacity to dampen responses to psychological and cellular stress. Targeting the cannabinoid system by influencing endogenous processes or exogenously stimulating cannabinoid receptors with natural or synthetic cannabis compounds has been identified as a promising route for Alzheimer’s Disease intervention. We build on our foundational framework focusing on the significance of chronic psychological and cellular stress on the development of Alzheimer’s neuropathology by integrating literature on cannabinoid function and dysfunction within Alzheimer’s Disease and conclude with remarks on optimal strategies for treatment potential.
... CB1 and CB2 receptors are present in a reduced number in those afflicted with AD. Research suggests that activating both these receptors by natural or synthetic agonists at small doses reduces Aβ aggregates and tau phosphorylation, and elicits a brain repair cascade [230][231][232]. Aβ plaque removal has also been attributed to these agonists, so many agonists, such as arachidonyl-2-chloroethylamide and β caryophyllene (Fig. 10), have been investigated in preclinical studies to alleviate neurodegeneration and neuroinflammation, and improve learning and memory [96,[233][234][235][236][237][238]. ...
Background: Alzheimer's disease (AD), the primary cause of dementia, escalating worldwide, has no proper diagnosis or effective treatment. Neuronal cell death and impairment of cognitive abilities, possibly triggered by several brain mechanisms, are the most significant characteristic of this disorder. Methods: A multitude of pharmacological targets have been identified for potential drug design against AD. Although many advances in treatment strategies have been made to correct various abnormalities, these often exhibit limited clinical significance because this disease aggressively progresses into different regions of the brain, causing severe deterioration. Results: So these biomarkers can be game-changers for early detection and timely monitoring of such disorders. Conclusion: This review covers clinically significant biomarkers of AD for precise and early monitoring of risk factors and stages of this disease, the potential site of action and novel targets for drugs, and pharmacological approaches to clinical management.
... Superoxide anion can induce the expression of CB1 (Wang et al., 2014). CB1 has been sown to be upregulated in Parkinson's Disease patients and postmortem brain from AD patients (Brotchie, 2003;Aso and Ferrer, 2014), both diseases where oxidative stress plays an important pathophysiological role. Some redox-sensitive transcription factors, such as AP-1, Nrf2, NFκB, and STATs, can upregulate the expression of proteins involved in eCB signaling, including CB1 and FAAH (Maccarrone et al., 2003a,b;Börner et al., 2008;Hsu et al., 2018;Galán-Ganga et al., 2020;Hay et al., 2020) although most of these effects were not experimentally observed under oxidative stress conditions. ...
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N -acyl amides (NAAs) are a class of lipids that consist of an acyl group N-linked to an amino acid, neurotransmitter, taurine or ethanolamide group ( N -acylethanolamines or NAEs) and include some endocannabinoids (eCB) such as anandamide. These lipids are synthesized in a wide variety of organisms and in multiple cell types, including neurons. NAEs are involved in numerous cellular and physiological processes and their concentrations are elevated in response to ischemia and physical trauma to play a role in neuroprotection. The neuroprotective properties of eCB NAEs make the protein targets of these compounds attractive targets for clinical intervention for a variety of conditions. The most promising of these targets include cannabinoid receptor type 1 (CB1), cannabinoid receptor type 2 (CB2), fatty acid amide hydrolase (FAAH), N -acylethanolamine acid amidase (NAAA), and N -acyl phosphatidylethanolamine phospholipase D (NAPE-PLD). Further characterization of these targets in a more contemporary model system of neurodegeneration and neuroprotection will allow us to fully describe their role and mechanism of action in neuroprotection against oxidative stress leading to better utilization in the clinical setting. Human stem cell-derived or human neural progenitor cell-derived cells, such as ReN cells, have become more utilized for the study of human neuronal development and neurodegenerative diseases. ReN cells can be easily differentiated thereby circumventing the need for using transformed cell lines and primary neurons as cell model systems. In this study, we determined whether ReN cells, a superior cell model system for studying neurodevelopment, differentiation, and neuroprotection, express proteins involved in canonical eCB NAE signaling and whether oxidative stress can induce their expression. We determined that sublethal oxidative stress upregulates the expression of all eCB proteins tested. In addition, we determined that oxidative stress increases the nuclear localization of FAAH, and to a lesser extent, NAAA and NAPE-PLD. This study is a first step toward determining how oxidative stress affects CB1, CB2, FAAH, NAAA, and NAPE-PLD expression and their potential defense against oxidative stress. As such, our data is important for further determining the role of eCB metabolizing proteins and eCB receptors against oxidative stress.
Endocannabinoid signalling plays an important role in affect, anxiety, and reward, and thus targeting this system could potentially be used to treat mental health and substance use disorders. This chapter discusses the current state of the clinical evidence evaluating the potential of various cannabinoid drugs as mental health and addiction pharmacotherapy, with a focus on randomized controlled trials. A few small clinical trials have found preliminary evidence for different cannabinoids in mental health disorders, including cannabidiol (CBD) for anxiety disorders, and Δ9-tetrahydrocannabinol (THC) for post-traumatic stress disorder (PTSD) and Tourette syndrome. The evidence for cannabinoids in other mental health conditions (e.g., psychotic disorders) is mixed. The clinical evidence also suggests that a combination of CBD and THC may be useful in reducing cannabis craving and/or withdrawal in patients with cannabis use disorder (CUD), with possible longer-term effects on reducing cannabis use and promoting abstinence. CBD alone may have the potential to reduce cannabis use, promote tobacco smoking cessation, and attenuate opioid craving, though these findings need replication. Finally, the cannabinoid type-1 (CB1) receptor antagonist rimonabant showed promise as a smoking cessation pharmacotherapy, yet this drug was withdrawn from the market due to serious psychiatric adverse effects. The current evidence demonstrates the potential for cannabinoid drugs in the treatment of mental health and substance use disorders, yet this evidence is clearly in its early stages. Future directions for the field are discussed.
Background Neurodegenerative diseases and dementia pose a global health challenge in an aging population, exemplified by the increasing incidence and prevalence of its most common form, Alzheimer's disease. Although several approved treatments exist for Alzheimer's disease, they only afford transient symptomatic improvements and are not considered disease-modifying. The psychoactive properties of Cannabis sativa L. have been recognized for thousands of years and now with burgeoning access to medicinal formulations globally, research has turned to re-evaluate cannabis and its myriad phytochemicals as a potential treatment and adjunctive agent for neurodegenerative diseases. Purpose This review evaluated the neuroprotective potential of C. sativa’s active constituents for potential therapeutic use in dementia and Alzheimer's disease, based on published studies demonstrating efficacy in experimental preclinical settings associated with neurodegeneration. Study Design Relevant information on the neuroprotective potential of the C. sativa’s phytoconstituents in preclinical studies (in vitro, in vivo) were included. The collated information on C. sativa’s component bioactivity was organized for therapeutic applications against neurodegenerative diseases. Methods The therapeutic use of C. sativa related to Alzheimer's disease relative to known phytocannabinoids and other phytochemical constituents were derived from online databases, including PubMed, Elsevier, The Plant List (TPL,, Science Direct, as well as relevant information on the known pharmacological actions of the listed phytochemicals. Results Numerous C. sativa -prevalent phytochemicals were evidenced in the body of literature as having efficacy in the treatment of neurodegenerative conditions exemplified by Alzheimer's disease. Several phytocannabinoids, terpenes and select flavonoids demonstrated neuroprotection through a myriad of cellular and molecular pathways, including cannabinoid receptor-mediated, antioxidant and direct anti-aggregatory actions against the pathological toxic hallmark protein in Alzheimer's disease, amyloid β. Conclusions These findings provide strong evidence for a role of cannabis constituents, individually or in combination, as potential neuroprotectants timely to the emergent use of medicinal cannabis as a novel treatment for neurodegenerative diseases. Future randomized and controlled clinical studies are required to substantiate the bioactivities of phytocannabinoids and terpenes and their likely synergies.
This reference is the definitive guide to common neurodegenerative diseases that affect humans. The book covers mechanisms of some of the most well-known neurodegenerative diseases, their biomarkers, neuropharmacology, and emerging treatment strategies. The book introduces the subject of neurodegeneration by outlining the biochemistry, pathophysiology and multifactorial neurological mechanisms (the role of genetics, environmental factors and mitochondrial damage, for example). Next, it explains some of the most studied diseases, namely, Parkinson's Disease, Alzheimer's Disease, Huntington’s Disease, and Multiple Sclerosis. Subsequent chapters delve into current knowledge about diagnostic and immunological biomarkers, followed by a summary of novel therapeutic strategies. Special attention has been given to the role of medicinal plants in attempting to treat neurodegenerative diseases, as well as the public health burden posed by these conditions. Key Features - give readers an overview of multifactorial disease mechanisms in neurodegeneration - covers some major neurodegenerative diseases in detail - covers diagnostic and immunological biomarkers - explores current therapeutic strategies and drug targets in common neurodegenerative diseases - offers a simple presentation with references for advanced readers The book is a suitable reference for all readers, including students, research scholars, and physicians who are interested in the mechanisms and treatment of neurodegenerative diseases.
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The primary psychoactive ingredient in cannabis, Δ^9-tetrahydrocannabinol (Δ^9-THC), affects the brain mainly by activating a specific receptor (CB1). CB1 is expressed at high levels in many brain regions, and several endogenous brain lipids have been identified as CB1 ligands. In contrast to classical neurotransmitters, endogenous cannabinoids can function as retrograde synaptic messengers: They are released from postsynaptic neurons and travel backward across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release. Cannabinoids may affect memory, cognition, and pain perception by means of this cellular mechanism.
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Emerging evidence suggests beta-amyloid (Aβ) deposition in the Alzheimer's disease (AD) brain is the result of impaired clearance, due in part to diminished Aβ transport across the blood-brain barrier (BBB). Recently, modulation of the cannabinoid system was shown to reduce Aβ brain levels and improve cognitive behavior in AD animal models. The purpose of the current studies was to investigate the role of the cannabinoid system in the clearance of Aβ across the BBB. Using in vitro and in vivo models of BBB clearance, Aβ transit across the BBB was examined in the presence of cannabinoid receptor agonists and inhibitors. In addition, expression levels of the Aβ transport protein, lipoprotein receptor-related protein1 (LRP1), were determined in the brain and plasma of mice following cannabinoid treatment. Cannabinoid receptor agonism or inhibition of endocannabinoid-degrading enzymes significantly enhanced Aβ clearance across the BBB (2-fold). Moreover, cannabinoid receptor inhibition negated the stimulatory influence of cannabinoid treatment on Aβ BBB clearance. Additionally, LRP1 levels in the brain and plasma were elevated following cannabinoid treatment (1.5-fold), providing rationale for the observed increase in Aβ transit from the brain to the periphery. The current studies demonstrate, for the first time, a role for the cannabinoid system in the transit of Aβ across the BBB. These findings provide insight into the mechanism by which cannabinoid treatment reduces Aβ burden in the AD brain and offer additional evidence on the utility of this pathway as a treatment for AD.
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Lipid rafts are membrane microdomains intimately associated with cell signaling. These biochemical microstructures are characterized by their high contents of sphingolipids, cholesterol and saturated fatty acids and a reduced content of polyun-saturated fatty acids (PUFA). Here, we have purified lipid rafts of human frontal brain cortex from normal and Alzheimer's disease (AD) and characterized their biochemical lipid composition. The results revealed that lipid rafts from AD brains exhibit aberrant lipid profiles compared to healthy brains. In particular, lipid rafts from AD brains displayed abnormally low levels of n-3 long chain polyunsaturated fatty acids (LCPUFA, mainly 22:6n-3, docosahexaenoic acid) and monoenes (mainly 18:1n-9, oleic acid), as well as reduced unsaturation and peroxidability indexes. Also, multiple relationships between phospholipids and fatty acids were altered in AD lipid rafts. Importantly, no changes were observed in the mole percentage of lipid classes and fatty acids in rafts from normal brains throughout the lifespan (24–85 years). These indications point to the existence of homeostatic mechanisms preserving lipid raft status in normal frontal cortex. The disruption of such mechanisms in AD brains leads to a considerable increase in lipid raft order and viscosity, which may explain the alterations in lipid raft signaling observed in AD.
Neuropathologic hallmarks of Alzheimer’s disease (AD) include the progressive deposition of virtually insoluble proteinaceous material in both extracellular and intraneuronal locations. The extracellular deposits consist mainly of Aβ-amyloid-protein (Joachim and Selkoe, 1989; Beyreuther and Masters, 1991; Selkoe, 1991, 1993, 1994); abnormally phosphorylated tau protein (PHF-tau, paired helical filament tau) dominates among the intraneuronal changes (Goedert et al., 1991, 1992; Iqbal and Grundke-Iqbal, 1991; Schmidt et al., 1991; Dickson et al., 1992; Goedert, 1993; Iqbal et al., 1993, 1994; Price and Sisodia, 1994; Trojanowski et al., 1995). A variety of other substances accompany both the Aβ-amyloid deposits and the abnormal tau protein.
Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here, we show that synaptic and cognitive impairments following repeated exposure to Δ(9)-tetrahydrocannabinol (Δ(9)-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids in the brain. COX-2 induction by Δ(9)-THC is mediated via CB1 receptor-coupled G protein βγ subunits. Pharmacological or genetic inhibition of COX-2 blocks downregulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ(9)-THC exposures. Ablation of COX-2 also eliminates Δ(9)-THC-impaired hippocampal long-term synaptic plasticity, working, and fear memories. Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ(9)-THC in Alzheimer's disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2.
The endocannabinoid system (ECS) is an important modulatory and potentially neuroprotective homeostatic system in the brain. In Alzheimer's disease (AD), the role of type 1 cannabinoid receptor (CB1R) is unclear, with contradictory findings in post-mortem studies showing upregulation, downregulation or unchanged CB1R status. We have investigated CB1R availability in vivo in patients with AD, in relation to amyloid deposition, cognitive functioning and apolipoprotein E (ApoE) genotype. Eleven AD patients and 7 healthy volunteers (HV) underwent combined [(18)F]MK-9470 PET and [(11)C]PIB PET scans to assess CB1R availability and amyloid deposition, respectively, and T1 volumetric MRI for partial volume correction. We found no difference in CB1R availability between AD and HV, VOI-based fractional uptake values (FUR) were 0.043±0.01 for AD and 0.045±0.01 for controls (p=0.9). CB1R availability did not correlate with neuropsychological test scores and was not modulated by ApoE genotype. As expected, global [(11)C]PIB SUVR (standardized uptake value ratio) was increased in AD (SUVR 1.9±0.3) compared to HV (1.2±0.1) with p<0.001, but no correlation was found between amyloid β (Aβ) deposition and CB1R availability. In conclusion, we found no in vivo evidence for a difference in CB1R availability in AD compared to age-matched controls. Taken together with recently reported in vivo CB1R changes in Parkinson's and Huntington's disease, these data suggest that the CB1R is differentially involved in neurodegenerative disorders.
Cannabinoid (CB) ligands have demonstrated neuroprotective properties. In this study we compared the effects of a diverse set of CB ligands against β amyloid-mediated neuronal toxicity and activated microglial-conditioned media-based neurotoxicity in vitro, and compared this with a capacity to directly alter β amyloid (Aβ) fibril or aggregate formation. Neuroblastoma (SH-SY5Y) cells were exposed to Aβ1-42 directly or microglial (BV-2 cells) conditioned media activated with lipopolysaccharide (LPS) in the presence of the CB1 receptor-selective agonist ACEA, CB2 receptor-selective agonist JWH-015, phytocannabinoids Δ(9)-THC and cannabidiol (CBD), the endocannabinoids 2-arachidonoyl glycerol (2-AG) and anandamide or putative GPR18/GPR55 ligands O-1602 and abnormal-cannabidiol (Abn-CBD). TNF-α and nitrite production was measured in BV-2 cells to compare activation via LPS or albumin with Aβ1-42. Aβ1-42 evoked a concentration-dependent loss of cell viability in SH-SY5Y cells but negligible TNF-α and nitrite production in BV-2 cells compared to albumin or LPS. Both albumin and LPS-activated BV-2 conditioned media significantly reduced neuronal cell viability but were directly innocuous to SH-SY5Y cells. Of those CB ligands tested, only 2-AG and CBD were directly protective against Aβ-evoked SH-SY5Y cell viability, whereas JWH-015, THC, CBD, Abn-CBD and O-1602 all protected SH-SY5Y cells from BV-2 conditioned media activated via LPS. While CB ligands variably altered the morphology of Aβ fibrils and aggregates, there was no clear correlation between effects on Aβ morphology and neuroprotective actions. These findings indicate a neuroprotective action of CB ligands via actions at microglial and neuronal cells.