REVIEW

Hidden defenses - A review of cannabinoid-receptor 1 and its

function in Alzheimers disease
B Parkins, E Gonzalez, J Serrano

College of Natural Sciences and Mathematics, California State University, Fullerton, CA
Alzheimers disease is a debilitating and progressing neurodegenerative disorder that displays
incredible cognitive impairment. The formation of hard plaques in neural tissue is a hallmark of
this disease, and the effects of these plaques are both irreversible and fatal. Recent studies have
linked an inverse relationship between the severity of the disease and the distribution of the
cannabinoid receptor CB
1
throughout the temporal and prefrontal cortex of the brain in patients
suffering from this disease. Here, we discuss a combination of theories for the progression of
Alzheimers, and the possible role these receptors may have in mitigating the damage.

Introduction
Cannabinoid receptor 1 (CB
1
) is one of the most abundant G protein-coupled receptors in
the nervous system (Faraks, et al., 2012). These receptors are known to have positive effects
when induced by triggering anti-inflammatory and neurotropic reactions in the nervous system
(Lee, et al., 2010). In addition to these responses, there is some evidence of interaction with
other diseases such as Alzheimer's. In this review, we discuss current knowledge and competing
theories for the pathology of these diseases, as well as the benefits of CB
1
modulation in relation
to these diseases.
CB
1
is widespread, its functions diverse
CB
1
is an important type of G-coupled proteins as it is the focal point for initiating a
series of molecular events that ultimately invoke a physiological response. Its position in the
extracellular cavity allows it to selectively bind to different types of ligands. The binding of
ligands causes a variety of outcomes as CB
1
is generally found in different isoforms and can be
coupled with homo and herterodimerized receptors (Turu & Hunyady, 2009). This ultimately
explains the association of CB
1
with different families of G-protein mediators that are essential
for the activation and deactivation of secondary molecules such as adenylyl cyclase, mitogen-
activated protein kinase (MAPK) and cyclic adenosine monophosphate (cAMP) (Turu &
Hunyady, 2009). These secondary mediators play a pivotal role as they lead to the manipulation
of DNA transcription or basal activity to produce a response (Turu & Hunyady, 2009).
Responses can be observed in neural, peripheral and endocrine cells as CB
1
is predominantly
found there. For this reason the intercellular signaling pathway of CB
1
is a growing field of study
as it shows therapeutic potential for a variety of diseases.
The pathology of Alzheimer's disease
A recent topic of interest is the interaction between Alzheimers disease (AD) and CB
1
.
Nitric oxide (NO), an important cellular signaling molecule, plays a fundamental role in AD
pathology (Knowles & Moncada, 1994). Nitric oxide synthase (NOS) catalyzes the production of
NO from L-arginine, and the inducible NOS (iNOS) is involved in immune response (Stuehr,
1999). iNOS produces large amounts of NO in response to cytokines and immune signals such
as those elicited from parasites, bacterial infection and tumor growth, in an effort to destroy any
pathogens that are both able to escape detection by the autoimmune system and cross the blood-
brain barrier. Unfortunately, since NO is a free radical, a large release of this molecule is likely
to cause significant collateral damage and thus display function as a "weapon of last resort."
Amyloid-beta (A) is the primary peptide involved in plaque formation typically seen in
AD. While the normal function of A is poorly understood (Hiltunen, van Groen, & Jolkkonen,
2009), it has been shown to mitigate oxidative stress in cell-free systems (Baruch-Suchodolsky &
Fischer, 2009), which may serve as a link between iNOS activity and A formation.
Additionally, A exhibits antimicrobial activity via a pro-inflammatory response (Soscia, et al.,
2010). The role of A in AD, however, is well understood; the misfolding of A leads to plaque
formation in the brain, and this triggers a cascade of local A to become misfolded. It is also
suggested that the misfolding of A can induce misfolding in tau proteins (Nussbaum, Seward,
& Bloom, 2013).
Tau proteins are responsible for stabilizing axonal microtubules. In most AD patients,
these proteins create tangles of paired helical filaments (PHF) and straight filaments (SF) in
amyloid plaques through hyperphosphorylation (Alonso, Zaidi, Novak, Grundke-Iqbal, & Iqbal,
2001). Misfolded proteins can influence normal local tau proteins to misfold and
hyperphosphorylate as well (Hall & Patuto, 2012), similar to the actions of misfolded A
oligomers. While normal proteins are quite soluble, the misfolded proteins are highly insoluble,
contributing to the production of plaques in the brain of AD patients. It is thought that
extracellular release of tau proteins by exosomes is responsible for an increase in abundance of
tau far above the extremely low levels seen in the central nervous system (Hall, Saman, & Lee,
2005).
Figure 1. Suggested pathological mechanism combining both the amyloid hypothesis and tau hypothesis
for plaque formation in AD patients.

Thus, it's possible to infer that iNOS may play some role in activation of A (Fig. 1) as a
response to free radical NO, as well as triggering hyperphosphorylation of tau proteins (Saez,
Pehar, Vargas, Barbeito, & Maccioni, 2004). Misfolding of A as a result of age, along with its
own influence on tau protein misfolding, leads to the formation of PHF/SF and amyloid plaques
in the brain of patients with AD. Due to the abundance of CB
1
in neural tissue, its anti-
inflammatory action and its ability to inhibit A-induced iNOS protein expression and tau
protein hyperphosphorylation (Esposito, et al., 2006), CB
1
agonists warrant further investigation
in the management and treatment of AD.
CB
1
is classified as a diverse set of G-coupling proteins that influence a network of
different molecular pathways. Patients with Alzheimer disease show no attenuation of CB
1

regardless of age and progression of the disease. Mulder et al. (2009) suggests signaling
modulation of the CB
1
molecular pathway to induce the expression of monoacylglycerol lipases.
These lipases will regulate the high concentrations of 2-arachidonoyl glycerol brought on by
Alzheimers disease which stimulates the synaptic affects of A. This regulation will inhibit the
primarily mechanism for the production of senile plagues and can prevent cognitive degradation.
CB
1
and cognitive function in patients with Alzheimers disease
A study performed by Faraks et. al (2012) compared cognitive abilities to CB
1
saturation
using brain slices from AD patients that had undergone extensive cognitive testing before death.
Normal brain cells from patients that had no neurological disorder related death served as a
control. Different samples of brain cells that were in different stages of AD were either lysed
and centrifuged or sliced thin and placed on glass slides. Immunoblotting of both control and
AD cells was performed using CB
1
antibodies. Other cells were radioactively incubated with
[
125
I]SD-7015, a CB
1
radioligand. Both the antibody and the radioligand were used to determine
the concentration of CB
1
in the control and AD brain cells.
Immunoblotting showed higher levels of CB
1
in the frontal cortex (Lee, et al., 2010).
Statistical analysis of these results concluded that there was a correlation between frontal cortex
CB
1
and increased cognitive abilities. Other results showed CB
1
density decreases in prefrontal
cortex compared to control in all stages of AD (Faraks, et al., 2012). These results also showed
that as the AD stages increased (Braak I-VI, in increasing severity), CB
1
levels decreased (Fig.2).











Discussion and Future Studies
With recent legislation regarding marijuana and in-depth analysis of the CB
1
agonists and
antagonists it contains, the importance of CB
1
in the human body is a focus of many current
studies. While the specific mechanisms involving CB
1
and its function in mitigating AD-related
neural damage are poorly understood, what is known about CB
1
signaling shows great promise
(Lee, et al., 2010). These studies show that there is a continuing need to understand CB
1

Figure 2. Autoradiograph using [
125
I]-SD-7015 as a radioligand in prefrontal cortex samples.
Both the third and fourth column show specific binding but the fourth was weighted. Red
arrows are white matter and black arrows are cortex. (Lee, et al., 2010)

pathways and their effects, and future studies could provide insights into the control and
treatment of AD. Current research suggests that the application of CB
1
ligands may help stem
the damage from neurodegenerative diseases like AD.
Since proteins such as A and iNOS exhibit pro-inflammatory function, it stands to
reason that the anti-inflammatory function of CB
1
would lessen the damage. Additionally, the
correlation between the saturation of CB
1
and absence of A plaques in neural tissues of AD
patients, while not completely definitive, warrants further investigation. Natural and synthetic
cannabinoids may soon become both an effective and cost-efficient method of treatment for this
debilitating and fatal disease.
Further research is needed to elucidate the exact mechanism for interaction between CB
1

and the plaques formed by misfolded A and tau proteins. While the function of iNOS in the
production of misfolded A proteins is yet to be determined, their influence on tau protein
proliferation and eventual hyperphosphorylation in a prion-like manner suggests they may be
partly responsible. In vivo studies will ultimately be required to determine the efficacy of CB
1

ligands in reducing the cognitive and physiological aspects of AD.

References
Alonso, A., Zaidi, T., Novak, M., Grundke-Iqbal, I., & Iqbal, K. (2001, Jun). Hyperphosphorylation induces self-
assembly of into tangles of paired helical filaments/straight filaments. PNAS, 98(12), pp. 6923-6928.
Baruch-Suchodolsky, R., & Fischer, B. (2009, May). Abeta40, either soluble or aggregated, is a remarkably potent
antioxidant in cell-free oxidative systems. Biochemistry, 48(20), pp. 4354-4370.
Esposito, G., De Filippis, D., Steardo, L., Scuderi, C., Savani, C., Cuomo, V., & Iuvone, T. (2006). CB1 receptor
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