A two-week course of high doses of CBD helped restore the function of two essential proteins to reduce the accumulation of beta-amyloid plaque, a hallmark of Alzheimer’s disease, and improve cognition in an experimental model of early-onset Alzheimer’s early – a way of Doctors know for sure that Alzheimer’s is linked to genes, the researchers report.
The TREM2 and IL-33 proteins are important to the ability of brain immune cells to literally consume dead cells and other debris like the beta-amyloid plaque that accumulates in patients’ brains – and both levels decrease in Alzheimer’s.
Researchers report for the first time that CBD normalizes levels and functions, improving cognition by more than seven times as it reduces levels of the IL-6 immune protein in mice, which is associated with the high levels of inflammation found in Alzheimer’s, says Dr. Babak Baban, immunologist and associate dean of research at Dental College of Georgia and corresponding author of the study.
He joined colleagues at the Medical College of Georgia, writing on Journal of Alzheimer’s Disease.
“We currently have two classes of drugs to treat Alzheimer’s disease,” says Dr. John Morgan, a neurologist and director of the Movement and Memory Disorders Programs at the MCG’s Department of Neurology. One class increases the levels of the neurotransmitter acetylcholine, which also decreases in Alzheimer’s, and another acts through NMDA receptors involved in communication between neurons and important for memory.
“But we have nothing to achieve the pathophysiology of the disease,” wrote the co-author.
The DCG and MCG researchers decided to examine the CBD’s ability to deal with some of the major brain systems that go wrong in Alzheimer’s.
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They found that CBD appears to normalize levels of IL-33, a protein whose highest expression in humans is normally in the brain, where it helps to sound the alarm that there is an invader like the accumulation of beta-amyloid. There is emerging evidence of its role as a regulatory protein as well, whose role in increasing or decreasing the immune response depends on the environment, Baban said.
In Alzheimer’s, this includes reducing inflammation and trying to restore the balance of the immune system. That up-and-down expression in health and disease could make IL-33 a good biomarker and treatment target for disease, say the researchers.
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CBD also improved expression of the triggering receptor expressed in myeloid cells 2, or TREM2, which is found on the cell surface where it combines with another protein to transmit signals that activate cells, including immune cells. In the brain, its expression is in microglial cells, a special population of immune cells found only in the brain, where they are essential to eliminate invaders such as a virus and irrevocably damaged neurons.
Low levels of TREM2 and rare variations of TREM2 are associated with Alzheimer’s and, in their experiments with mice, supported by the National Institutes of Health, TREM2 and IL-33 were both low.
Increasing Useful Proteins 7 and 10 times
They found that CBD treatment increased levels of IL-33 and TREM2 – seven and ten times, respectively.
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Both are essential for a process of natural and continuous maintenance in the brain called phagocytosis, in which microglia cells regularly consume beta amyloid, which is regularly produced in the brain, the result of the breakdown of the beta-amyloid precursor protein, which is important for the synapses, or connection points, between neurons and that the plate interrupts.
The impact of CBD on brain function in the early-onset Alzheimer’s rat model was assessed by methods such as the ability to differentiate between a familiar item and a new one, as well as to observe the movement of rodents.
People with Alzheimer’s can have movement problems like stiffness and difficulty walking, says Dr. Hesam Khodadadi, a graduate student who works in Baban’s laboratory. Mice with the disease run in a never-ending narrow circle, a behavior that stopped CBD treatment, says Khodadadi, the study’s first author.
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The next steps include determining the ideal doses and administering CBD early in the disease process. The compound was administered in the final stages of the published study and researchers are now using it at the first signs of cognitive decline, says Khodadadi. They are also exploring delivery systems, including the use of an inhaler that should help deliver CBD more directly to the brain. For the published studies, CBD was placed in the belly of the rats every other day for two weeks.
One company has developed animal and human inhalers for researchers who have also explored the effect of CBD on adult respiratory distress syndrome, or ARDS, an accumulation of fluid in the lungs that is an important and deadly complication of COVID-19, as well as others serious illnesses, such as sepsis and severe trauma. The doses of CBD used for the Alzheimer’s study were the same as the ones the researchers used successfully to reduce the ARDS “cytokine storm”, which can irrevocably damage the lungs.
Familial disease is a hereditary version of Alzheimer’s disease, in which symptoms usually appear between the ages of 30 and 40 and occur in about 10-15% of patients.
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CBD should be at least equally effective in the most common and unfamiliar type of Alzheimer’s, which is likely to have more targets for CBD, notes Baban. They are already analyzing its potential in a model of this more common type and moving forward to establish a clinical trial.
Plaques, as well as neurofibrillary tangles, a collection of the tau protein within neurons, are the main components of Alzheimer’s, says Morgan. Beta-amyloid usually appears in the brain 15-20 years or more before dementia, he says, and the appearance of tangles of tau, which can occur up to 10 years later, correlates with the onset of dementia. There is some interaction between beta amyloid and tau that lessens one’s dysfunction, notes Morgan.
The Food and Drug Administration is scheduled to make a decision in early June on a new aducanumab drug, which would be the first to attack and help eliminate beta-amyloid, says Morgan.
(Source: Augusta University media)
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