Alzheimer’s disease has been described in medical literature for more than a century, but still has no effective treatments. Now, scientists at the Salk Institute in La Jolla, California, report finding evidence that tetrahydrocannabinol (THC), one of several physiologically active chemical compounds in marijuana, can promote cellular removal of amyloid beta, a toxic protein associated with Alzheimer’s disease.
While these exploratory studies were conducted with neurons grown in a laboratory, the researchers suggest they may offer insights into the role inflammation plays in Alzheimer’s disease, and even point the way to developing therapeutic agents to treat this complex disorder.
In a paper published in the journal Aging and Mechanisms of Disease, the Salk research team describes how they studied nerve cells altered to produce high levels of amyloid beta to mimic aspects of Alzheimer’s disease. The paper, “Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids“ (Aging and Mechanisms of Disease, 2016; 2: 16012 DOI: 10.1038/npjamd.2016.12), notes that it is well-known that amyloid beta begins accumulating within nerve cells of the aging brain well before Alzheimer symptoms or plaques are evident, but the mechanistic relationship between intracellular amyloid, aging, and neurodegeneration is not well understood. (Amyloid beta is a major component of the plaque deposits.)
“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 amyloid beta accumulation in nerve cells,” Salk Professor David Schubert, the paper’s senior author, said in a press release.
The Salk researchers found that high levels of amyloid beta accumulation were associated with cellular inflammation and higher rates of neuron death in the brain — a major component of the damage associated with Alzheimer’s disease. Exposing the nerve cells to THC reduced amyloid beta protein levels, and stopped the inflammatory response caused by the amyloid protein, allowing the cells to survive.
“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,” said Antonio Currais, a postdoctoral researcher in the Schubert laboratory at Salk and the study’s first author. “When we were able to identify the molecular basis of the inflammatory response to amyloid beta, it became clear that THC-like compounds that the nerve cells make themselves may be involved in protecting the cells from dying.”
Receptors in brain cells act as “switches” that can be activated by endocannabinoids, a class of lipid molecules manufactured by the body that support intercellular signaling in the brain. Physical activity stimulates endocannabinoid production, and the scientists noted that some studies have shown exercise can help to slow the progression of Alzheimer’s disease. The psychoactive effects of marijuana are caused by THC, which is molecularly similar in activity to human endocannabinoids, and can activate the same receptors in the brain.
In separate but relevant research, the Schubert lab has developed an Alzheimer’s drug candidate called J147 that also removes amyloid beta from nerve cells and reduces inflammatory response in both nerve cells and the brain. When given to mice with Alzheimer’s, J147 was seen to improve memory and prevent brain damage caused by the disease. The researchers’ work with J147 led to the discovery that endocannabinoids can also remove amyloid beta and reduce inflammation. However, Schubert cautions that his team’s findings were conducted in exploratory laboratory models, and that the use of THC-like compounds as therapy for Alzheimer’s would first need to undergo testing in clinical trials.
The study received support from the National Institutes of Health, The Burns Foundation, and The Bundy Foundation.
According to the NIH, Alzheimer’s affects more than 5.4 million Americans, and is the most common cause of dementia. Its incidence, according to Alzheimer’s Association, is expected to triple to 16 million by 2050, resulting in projected medical costs of over $1 trillion per year during the next 50 years as the baby boom generation moves into old age.
Aging and Mechanisms of Disease
National Institutes of Health