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Prevention of Alzheimer's Disease

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Prevention of Alzheimer's Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation


Alzheimer's disease (AD) is characterized by enhanced β-amyloid peptide (βA) deposition along with glial activation in senile plaques, selective neuronal loss, and cognitive deficits. Cannabinoids are neuroprotective agents against excitotoxicity in vitro and acute brain damage in vivo. This background prompted us to study the localization, expression, and function of cannabinoid receptors in AD and the possible protective role of cannabinoids after βA treatment, both in vivo and in vitro. Here, we show that senile plaques in AD patients express cannabinoid receptors CB1 and CB2, together with markers of microglial activation, and that CB1-positive neurons, present in high numbers in control cases, are greatly reduced in areas of microglial activation. In pharmacological experiments, we found that G-protein coupling and CB1 receptor protein expression are markedly decreased in AD brains. Additionally, in AD brains, protein nitration is increased, and, more specifically, CB1 and CB2 proteins show enhanced nitration. Intracerebroventricular administration of the synthetic cannabinoid WIN55,212-2 to rats prevent βA-induced microglial activation, cognitive impairment, and loss of neuronal markers. Cannabinoids (HU-210, WIN55,212-2, and JWH-133) block βA-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor-α release; these effects are independent of the antioxidant action of cannabinoid compounds and are also exerted by a CB2-selective agonist. Moreover, cannabinoids abrogate microglia-mediated neurotoxicity after βA addition to rat cortical cocultures. Our results indicate that cannabinoid receptors are important in the pathology of AD and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.



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Alzheimer's disease (AD), the most common form of dementia, is characterized by the deposition of β-amyloid peptide (βA) within one of its pathological hallmarks: the senile plaque. Activated microglia cluster at senile plaques (McGeer et al., 1987; Dickson et al., 1988), and this seems to be responsible for the ongoing inflammatory process in the disease. Transgenic mouse models of AD also develop plaques in which βA deposits and activated microglia exist (Masliah et al., 1996; Frautschy et al., 1998; Jantzen et al., 2002). Furthermore, microglial activation results in neurodegeneration both in vitro (Meda et al., 1995; Gao et al., 2002; Xie et al., 2002) and in vivo (Weldon et al., 1998; Herrera et al., 2000; Iravani et al., 2002) paradigms. In this context, recent studies have focused on the therapeutic interest of limiting microglial activation and inflammation in AD and other neurological disorders.

Cannabinoids, the active components of marijuana and their analogs, exert a wide spectrum of central and peripheral effects by activating specific cannabinoid receptors, two of which have been well characterized to date: CB1 and CB2 (Howlett et al., 2002; Piomelli, 2003). CB1 receptors are found in high density in the nervous system (Herkenham et al., 1990), in which they mediate cannabinoid psychoactivity, and all types of neural cells express them. Thus, in addition to being present in neurons, CB1 receptors exist in astrocytes (Bouaboula et al., 1995; Sánchez et al., 1998), microglia (Waksman et al., 1999; Walter et al., 2003), and oligodendrocytes (Molina-Holgado et al., 2002). In contrast, the CB2 receptor is considered to be expressed solely in cells and organs of the immune system and is unrelated to cannabinoid psychoactivity. There are also recent reports on the existence of CB2 receptors in microglia (Walter et al., 2003) and on cannabinoids affecting migration (Walter et al., 2003), as well as nitric oxide (NO) and cytokine production (Waksman et al., 1999; Puffenbarger et al., 2000; Facchinetti et al., 2003) in microglial cell cultures in vitro.

Cannabinoids exert neuroprotection under different experimental conditions. Thus, cannabinoid receptor activation protects hippocampal or granule cerebellar neurons from excitotoxicity (Skaper et al., 1996; Shen and Thayer, 1998; Hampson and Grimaldi, 2001) and from hypoxia and glucose deprivation (Nagayama et al., 1999). In vivo, cannabinoids decrease hippocampal neuronal loss and infarct volume after cerebral ischemia (Nagayama et al., 1999), acute brain trauma (Panikashvili et al., 2001), and ouabain-induced excitotoxicity (van der Stelt et al., 2001). These effects have been ascribed to inhibition of glutamate transmission, reduction of calcium influx, and subsequent inhibition of noxious cascades, such as tumor necrosis factor-α (TNF-α) generation and oxidative stress.

This background prompted us to study the characteristics and localization of cannabinoid receptors in AD brain, with particular emphasis on any relationship with microglial activation. Furthermore, the effects of cannabinoid receptor activation were studied in an animal model of AD in vivo and in a model of βA-induced microglial activation in vitro.

Materials and Methods

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Very interesting!


When I was in the USN I was stationed in Key West, FL. I worked at the clinic at Naval Air Station on Big Coppitt Key just a few mile north of Key West. The hospital at Key West was for out patient only for retired armed forces personnel that lived in the area. If you needed to be hospitalized you were sent to Homestead AFB Florida. I had the day off and just went inside the hospital (Corpsman barracks were next to hospital). There was a retired navy man that worked in the lab and he was very interesting gentleman to talk with. He was a retired biochemist from the USN, he asked me what was going on that day and I said I had the day off. I wish I was working as the crew on today was taking a sailor to Homestead as he had a very bad kidney infection.


Now this elderly gent told me the man should have eaten more asparagus and he wouldn't have that problem. I asked why? I'll never forget him saying do you eat asparagus and I said yes, I love them. He replied you notice how your urine stinks after eating asparagus? I said well I never thought it was what I ate, but yes it does have a pungent odor. It is because it is detoxifying your body of harmful chemicals!!! This was back in 1986 when I was stationed there and to read this email again I had to share this story...Eat more asparagus my friends.


Asparagus -- Who knew?


My Mom had been taking the full-stalk canned style
asparagus, pureed it and took 4 tablespoons in
the morning and 4 tablespoons later in the day. She did
this for over a month. She is on chemo pills for Stage 3
lung cancer in the pleural area and her cancer cell
count went from 386 down to 125 as of this past week.
Her oncologist said she will not need to see him for 3


Several years ago I met a man seeking asparagus for a
friend who had cancer. He gave me a copy of an article,
entitled "Asparagus For Cancer" printed in the
Cancer News Journal, December 1979. I will share it
here, just as it was shared with me: I am a
biochemist, and have specialized in the relation of diet
to health or over 50 years. Several years ago, I learned
of the discovery of Richard R. Vensal, D.D.S. that
asparagus might cure cancer. Since then, I have worked
with him on his project. We have accumulated a number
of favorable case histories. Here are a few examples:


Case No. 1: A man with an almost hopeless case
of Hodgkin's disease (cancer of the lymph glands) who
was completely incapacitated. Within 1 year of starting
the asparagus therapy, his doctors were unable to
detect any signs of cancer, and he was back on a
schedule of strenuous exercise


Case No. 2: A successful businessman, 68 years old,
suffered from cancer of the bladder for 16 years.
After years of medical treatments, including radiation
without improvement, he began taking asparagus. Within 3 months, examinations revealed that his bladder tumor had disappeared and that his
kidneys were normal.


Case No. 3: On March 5th 1971, a man who had lung
cancer was put on the operating table where they found
lung cancer so widely spread that it was inoperable.
The surgeon sewed him up and declared his case
hopeless. On April 5th he heard about the Asparagus
therapy and immediately started taking it. By August,
x-ray pictures revealed that all signs of the cancer had
disappeared. He is now back at his regular business


Case No. 4: A woman had been troubled for a number of
years with skin cancer. She developed different skin cancers which were diagnosed by the acting specialist as advanced. Within 3 months after beginning asparagus therapy, the skin specialist said her skin looked fine with no more skin lesions. This woman reported that the asparagus therapy also cured her kidney disease, which had started in 1949. She had over 10 operations for kidney stones, and was receiving government disability payments for an inoperable, terminal, kidney condition. She attributes the cure of this kidney trouble entirely to the asparagus treatment.


I was not surprised at this result as `The elements of
materia medica', edited in1854 by a Professor at the
University of Pennsylvania, stated that asparagus was
used as a popular remedy for kidney stones. He even
referred to experiments, in 1739, on the power of
asparagus in dissolving stones. Note the dates!
We would have other case histories but the medical
establishment has interfered with our obtaining some
of the records. I am therefore appealing to readers to
spread this good news and help us to gather a large
number of case histories that will overwhelm the
medical skeptics about this unbelievably simple and
natural remedy.


For the treatment, asparagus should be cooked
before using. Fresh or canned asparagus can be
used. I have corresponded with the two leading canners
of asparagus, Giant and Stokely, and I am satisfied that
these brands contain no pesticides or preservatives.
Place the cooked asparagus in a blender and liquefy to
make a puree. Store in the refrigerator. Give the patient
4 full tablespoons twice daily, morning and evening.
Patients usually show some improvement in 2-4 weeks.
It can be diluted with water and used as a cold or hot drink.
This suggested dosage is based on present experience,
but certainly larger amounts can do no harm and may be needed in some cases.


As a biochemist I am convinced of the old saying that `what cures can prevent.' Based on this theory, my wife and I have been using asparagus
puree as a beverage with our meals. We take 2 tablespoons diluted in water to
suit our taste with breakfast and with dinner. I take
mine hot and my wife prefers hers cold. For years we
have made it a practice to have blood surveys taken as
part of our regular checkups. The last blood survey,
taken by a medical doctor who specializes in the
nutritional approach to health, showed substantial
improvements in all categories over the last one, and
we can attribute these improvements to nothing but
the asparagus drink. As a biochemist, I have made an
extensive study of all aspects of cancer, and all of the
proposed cures. As a result, I am convinced that
asparagus fits in better with the latest theories about cancer.


Asparagus contains a good supply of protein called
histones, which are believed to be active in controlling
cell growth. For that reason, I believe asparagus can
be said to contain a substance that I call cell growth
normalizer. That accounts for its action on cancer and
in acting as a general body tonic In any event,
regardless of theory, asparagus used as we suggest, is
a harmless substance. The FDA cannot prevent you
from using it and it may do you much good. It has
been reported by the US National Cancer Institute, that
asparagus is the highest tested food containing
glutathione, which is considered one of the body's
most potent anticarcinogens and antioxidants.


Just a side note... In case you are wondering why this has not been made public, there is no profit in curing cancer!


Please send this article to everyone in your Address Book. The most unselfish act one can ever do is paying forward all the kindness one has received.

A Posse ad Esse. From Possibility to realization.


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Say Graywolf. that is an excellent post. Im going to take it and make it its own post and topic,


It should not be left here hidden. :D


Thanks for this contribution.

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Remember that I am a beginning in this endeavor: I just found Granny Crow's list. Wow. She should win a Nobel prize at some point, IMO.

Edited by Kiley

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