Marijuana fights Alzheimer’s disease, Salk Institute scientists discover

Cannabinoids remove plaque-forming Alzheimer's proteins from brain cells

“Salk Institute scientists have discovered that a main compound found in marijuana can fight a toxic protein associated with Alzheimer’s disease. According to the scientists, at this time, there are no drugs that significantly inhibit cell death associated with Alzheimer’s disease (AD), Parkinson’s or Huntington’s diseases. However, the most recent data about Alzheimer’s and marijuana suggests that there is a therapeutic potential of cannabinoids (the chemical compounds secreted by cannabis flowers) for the treatment of AD. Cannabinoids are able to remove plaque-forming Alzheimer’s proteins from brain cells, reports the Medical Express on June 29.”  http://www.examiner.com/article/marijuana-fights-alzheimer-s-disease-salk-institute-scientists-discover

“Cannabinoids remove plaque-forming Alzheimer’s proteins from brain cells”  http://medicalxpress.com/news/2016-06-cannabinoids-plaque-forming-alzheimer-proteins-brain.html

“Cannabinoids remove toxic proteins associated with Alzheimer’s disease from the brain” http://www.irishexaminer.com/examviral/science-world/cannabinoids-remove-toxic-proteins-associated-with-alzheimers-disease-from-the-brain-407788.html

“Marijuana Compound Helps Remove Alzheimer’s Disease Protein From Brain” -brain.” http://www.scienceworldreport.com/articles/42990/20160630/marijuana-compound-helps-remove-alzheimers-disease-protein-from-brain.htm

“Marijuana compound removes toxic Alzheimer’s protein from the brain”  http://www.sciencealert.com/marijuana-compound-removes-toxic-alzheimer-s-protein-from-the-brain

“Cannabinoids remove plaque-forming Alzheimer’s proteins from brain cells”  https://www.sciencedaily.com/releases/2016/06/160629095609.htm

“Cannabinoids Remove Plaque-forming Alzheimer’s Proteins from Brain Cells”  https://www.laboratoryequipment.com/news/2016/06/cannabinoids-remove-plaque-forming-alzheimers-proteins-brain-cells

“MARIJUANA COMPOUND REMOVES ALZHEIMER’S PLAQUE FROM BRAIN CELLS, STUDY FINDS” http://www.popsci.com/marijuana-compound-removes-alzheimers-plaque-from-brain-cells-study

“Cannabinoids remove plaque-forming Alzheimer’s proteins from brain cells. Preliminary lab studies at the Salk Institute find THC reduces beta amyloid proteins in human neurons.” http://www.salk.edu/news-release/cannabinoids-remove-plaque-forming-alzheimers-proteins-from-brain-cells/

 

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Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids

“The beta amyloid (Aβ) and other aggregating proteins in the brain increase with age and are frequently found within neurons. The mechanistic relationship between intracellular amyloid, aging and neurodegeneration is not, however, well understood.

We use a proteotoxicity model based upon the inducible expression of Aβ in a human central nervous system nerve cell line to characterize a distinct form of nerve cell death caused by intracellular Aβ.

It is shown that intracellular Aβ initiates a toxic inflammatory response leading to the cell’s demise. Aβ induces the expression of multiple proinflammatory genes and an increase in both arachidonic acid and eicosanoids, including prostaglandins that are neuroprotective and leukotrienes that potentiate death.

Cannabinoids such as tetrahydrocannabinol stimulate the removal of intraneuronal Aβ, block the inflammatory response, and are protective.

Altogether these data show that there is a complex and likely autocatalytic inflammatory response within nerve cells caused by the accumulation of intracellular Aβ, and that this early form of proteotoxicity can be blocked by the activation of cannabinoid receptors.”

http://www.nature.com/articles/npjamd201612

“Cannabinoids remove plaque-forming Alzheimer’s proteins from brain cells. Preliminary lab studies at the Salk Institute find THC reduces beta amyloid proteins in human neurons.” http://www.salk.edu/news-release/cannabinoids-remove-plaque-forming-alzheimers-proteins-from-brain-cells/

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Expression of the endocannabinoid receptors in human fascial tissue.

“Cannabinoid receptors have been localized in the central and peripheral nervous system as well as on cells of the immune system, but recent studies on animal tissue gave evidence for the presence of cannabinoid receptors in different types of tissues.

Their presence was supposed also in myofascial tissue, suggesting that the endocannabinoid system may help resolve myofascial trigger points and relieve symptoms of fibromyalgia.

However, until now the expression of CB1 (cannabinoid receptor 1) and CB2 (cannabinoid receptor 2) in fasciae has not yet been established.

Small samples of fascia were collected from volunteers patients during orthopedic surgery. For each sample were done a cell isolation, immunohistochemical investigation (CB1 and CB2 antibodies) and real time RT-PCR to detect the expression of CB1 and CB2.

Both cannabinoid receptors are expressed in human fascia and in human fascial fibroblasts culture cells, although to a lesser extent than the control gene. We can assume that the expression of mRNA and protein of CB1 and CB2 receptors in fascial tissue are concentrated into the fibroblasts.

This is the first demonstration that the fibroblasts of the muscular fasciae express CB1 and CB2. The presence of these receptors could help to provide a description of cannabinoid receptors distribution and to better explain the role of fasciae as pain generator and the efficacy of some fascial treatments.

Indeed the endocannabinoid receptors of fascial fibroblasts can contribute to modulate the fascial fibrosis and inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/27349320

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The Cannabinoid Receptor 2 Protects Against Alcoholic Liver Disease Via a Macrophage Autophagy-Dependent Pathway.

“Kupffer cells, the resident macrophages of the liver, play a major role in the pathogenesis of alcoholic liver disease. We have previously demonstrated that CB2 receptor protects against alcoholic liver disease by inhibiting alcohol-induced inflammation and steatosis via the regulation of Kupffer cell activation.

Here, we explored the mechanism underlying these effects and hypothesized that the anti-inflammatory properties of CB2 receptor in Kupffer cells rely on activation of autophagy.

Altogether these results demonstrate that CB2 receptor activation in macrophages protects from alcohol-induced steatosis by inhibiting hepatic inflammation through an autophagy-dependent pathway.”

http://www.ncbi.nlm.nih.gov/pubmed/27346657

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Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB.

“One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is hydrolysis by fatty acid amide hydrolase (FAAH), and inhibitors of the enzyme were suggested as potential treatment for human cannabis dependence.

In cannabis users, FAAH binding was significantly lower by 14%-20% across the brain regions examined than in matched control subjects.

Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel treatment strategies for cannabis use disorder that target FAAH and endocannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/27345297

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Dissecting the signaling pathways involved in the crosstalk between mGlu5 and CB1 receptors.

“The metabotropic glutamate (mGlu) receptor 5 and the cannabinoid type 1 (CB1) receptor are G-protein-coupled receptors (GPCR) that are widely expressed in the central nervous system (CNS). mGlu5 receptors, present at the postsynaptic site, are coupled to Gαq/11 proteins and display an excitatory response upon activation, while the CB1 receptor, mainly present at presynaptic terminals, is coupled to the Gi/o protein and triggers an inhibitory response. Recent studies suggest that the glutamatergic and endocannabinoid systems exhibit a functional interaction to modulate several neural processes. In this review we discuss possible mechanisms involved in this crosstalk and its relationship with physiological and pathological conditions, including nociception, addiction and fragil X syndrome.”

http://www.ncbi.nlm.nih.gov/pubmed/27338080

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Anatomical characterization of the cannabinoid cb1 receptor in cell type-specific mutant mouse rescue models.

“Type-1 cannabinoid (CB1 ) receptors are widely distributed in the brain. Their physiological roles depend on their distribution pattern that differs remarkably among cell types. Hence, subcellular compartments with little but functional relevant CB1 receptors can be overlooked, fostering an incomplete mapping. To overcome this, knock-in mice with cell-type specific rescue of CB1 receptors have emerged as excellent tools to investigate its cell type-specific localization and sufficient functional role with no bias.

However, to know whether these rescue mice maintain endogenous CB1 receptor expression level, detailed anatomical studies are called for. The subcellular distribution of hippocampal CB1 receptors of rescue mice that express the gene exclusively in dorsal telencephalic glutamatergic neurons (Glu-CB1 -RS) or GABAergic neurons (GABA-CB1 -RS) was studied by immunoelectron microscopy. Results were compared with conditional CB1 receptor knock-out lines.

As expected, CB1immunoparticles appeared at presynaptic plasmalemma making asymmetric and symmetric synapses. In the hippocampal CA1 stratum radiatum, the values of the CB1 receptor immunopositive excitatory and inhibitory synapses were: Glu-CB1 -RS: 21.89% (glutamatergic terminals); 2.38% (GABAergic terminals); GABA-CB1 -RS: 1.92% (glutamatergic terminals); 77.92% (GABAergic terminals). The proportion of CB1 receptor immunopositive excitatory and inhibitory synapses in the inner third of the dentate molecular layer was: Glu-CB1 -RS: 53.19% (glutamatergic terminals); 2.30% (GABAergic terminals); GABA-CB1 -RS: 3.19% (glutamatergic terminals); 85.07% (GABAergic terminals).

Taken together, Glu-CB1 -RS and GABA-CB1 -RS mice show the usual CB1 receptor distribution and expression in hippocampal cell types with specific rescue of the receptor, being therefore ideal for in-depth anatomical and functional investigations of the endocannabinoid system.”

http://www.ncbi.nlm.nih.gov/pubmed/27339436

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The multiple waves of cannabinoid 1 receptor signaling.

“The cannabinoid 1 receptor (CB1R) is one of the most abundant G protein-coupled receptor (GPCR) in the CNS with key roles during neurotransmitter release and synaptic plasticity. Upon ligand activation, CB1Rs may signal in three different spatiotemporal waves.

The first wave is transient (<10 minutes) and is initiated by heterotrimeric G proteins followed by a second wave (>10 minutes) mediated by beta-arrestins. A final third wave occurs at intracellular compartments and could be elicited by G proteins or beta-arrestins.

This functional complexity presents multiple challenges, from the correct classification of receptor ligands to the identification of the signaling pathways regulated by each wave and their underlying molecular mechanisms and physiological impact.

Simultaneously, it provides new opportunities to harness the therapeutic potential of the cannabinoid system.

Over the last several years, we have significantly expanded our understanding of the mechanisms and pathways downstream from CB1R. The identification of mutations in the receptor that can bias signaling to specific pathways and the use of siRNA technology in combination with toxins have been key tools to identify which signaling cascades are controlled by G proteins or beta-arrestins.

Here, we review our current knowledge of the multiple waves of CB1R signaling with particular emphasis on the mechanisms and cascades mediated by beta-arrestins downstream from the CB1R.”

http://www.ncbi.nlm.nih.gov/pubmed/27338082

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Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer.

Image result for Oncotarget.“The orphan G protein-coupled receptor GPR55 has been directly or indirectly related to basic alterations that drive malignant growth: uncontrolled cancer cell proliferation, sustained angiogenesis, and cancer cell adhesion and migration. However, little is known about the involvement of this receptor in metastasis.

Here, we show that elevated GPR55 expression in human tumors is associated with the aggressive basal/triple-negative breast cancer population, higher probability to develop metastases, and therefore poor patient prognosis. Activation of GPR55 by its proposed endogenous ligand lysophosphatidylinositol confers pro-invasive features on breast cancer cells both in vitro and in vivo. Specifically, this effect is elicited by coupling to Gq/11 heterotrimeric proteins and the subsequent activation, through ERK, of the transcription factor ETV4/PEA3.

Together, these data show that GPR55 promotes breast cancer metastasis, and supports the notion that this orphan receptor may constitute a new therapeutic target and potential biomarker in the highly aggressive triple-negative subtype.”

http://www.ncbi.nlm.nih.gov/pubmed/27340777

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