Devotees and users of marijuana have expounded the medicinal benefits of the drug for centuries. Unfortunately, in recent decades marijuana use has been demonized by lawmakers, making it tough to sort out the vast number of potentially beneficial health claims from anecdotal ones. However now, Researchers from the Salk Institute have shown that tetrahydrocannabinol (THC) and other compounds found in marijuana can contribute to the removal of toxic proteins, known as amyloid-β (Aβ), which have been linked to Alzheimer’s disease. This research offers new insight into the role that inflammation plays in this neurological disorder, which could point the way to new drugs.
“Although other studies have offered evidence that cannabinoids might be neuroprotective against the symptoms of Alzheimer’s, we believe our study is the first to demonstrate that cannabinoids affect both inflammation and Aβ accumulation in nerve cells,” explained senior study author David Schubert, Ph.D., professor and laboratory head at the Salk Institute.
It has been known for some time that Aβ accumulates within nerve cells of the aging brain—often well before the appearance of Alzheimer’s disease symptoms and plaques. Aβ is a major component of the plaque deposits that are a hallmark of the disease. Yet, the precise role of Aβ and the plaques it forms in the disease process remains unclear.
The Salk team studied nerve cells in vitro that were engineered to produce high levels of Aβ to mimic aspects of Alzheimer’s disease and found that elevated levels of Aβ were associated with cellular inflammation and higher rates of neuron death. Interestingly the researchers found that exposing the cells to THC reduced Aβ protein levels and eliminated the inflammatory response from the nerve cells caused by the protein, thereby allowing the nerve cells to survive.
“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,” the authors wrote. “It is shown that intracellular Aβ initiates a toxic inflammatory response leading to the cell’s demise. …Cannabinoids such as tetrahydrocannabinol stimulate the removal of intraneuronal Aβ, block the inflammatory response, and are protective.”
The findings from this study were published recently in Aging and Mechanisms of Disease in an article entitled “Amyloid Proteotoxicity Initiates an Inflammatory Response Bocked by Cannabinoids.”
“Inflammation within the brain is a major component of the damage associated with Alzheimer’s disease, but it has always been assumed that this response was coming from immune-like cells in the brain, not the nerve cells themselves,” noted lead study author Antonio Currais, Ph.D., a postdoctoral researcher in Dr. Schubert’s laboratory. “When we were able to identify the molecular basis of the inflammatory response to Aβ, it became clear that THC-like compounds that the nerve cells make themselves may be involved in protecting the cells from dying.”
The endogenous THC-like compounds that Dr. Currais mentioned are called endocannabinoids, a class of lipid molecules made by the body that are used for intercellular signaling in the brain. A variety of brain cell receptors can be activated by endocannabinoid molecules. Moreover, the psychoactive effects of marijuana are caused by THC, a molecule similar in activity to the endocannabinoids that can activate the same receptors. Physical activity results in the production of endocannabinoids, and some studies have shown that exercise may slow the progression of Alzheimer’s disease—creating a causal link toward a potentially druggable biological pathway.
The researchers were excited by their findings, which arose from their earlier work on an Alzheimer’s drug candidate that also removes Aβ from nerve cells and reduces the inflammatory response in both nerve cells and the brain. However, the Salk researchers emphasized caution in overinterpretation, stating that their studies were conducted in exploratory laboratory models and that the use of THC-like compounds as a therapy would need to be tested in clinical trials.
“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,” the authors concluded.