CBD and the Brain: How Cannabidiol Slows Cognitive Decline in Alzheimer’s Disease
There is a dire need for innovative therapeutic modalities to improve outcomes of Alzheimer’s disease, which is characterized by a progressive decline in cognition and persistent deterioration of overall health. The changes that lead to the development of this complex form of dementia involve abnormal protein production, expression of certain receptors on nervous tissues, and a damaging neuroinflammatory response in the central nervous system.
The last few years have seen an increased interest in the therapeutic effects of cannabinoids like cannabidiol (CBD) on conditions such as epilepsy and Parkinson’s disease. Research shows that CBD can modulate immune and inflammatory responses that contribute to changes that lead to neurodegeneration. Since Alzheimer’s disease results from several neurodegenerative steps, researchers have proposed CBD as a possible therapy for prevention and treatment (1-3). But, if and how CBD improves outcomes in a translational model of familial Alzheimer’s disease is unclear.
Abnormal Protein Deposits and Inflammation Cause Neurodegeneration
Brain cells need special proteins called cytokines to communicate with each other to function cohesively. Researchers believe CBD may be useful in preserving brain health and cognition through the effects it has on cytokines — signaling molecules that immune cells secrete to talk to each other — and receptors on specialized brain cells.
The most abundantly available cytokine in the central nervous system is interleukin (IL)-33. Specialized nervous system cells called glial cells produce this cytokine, which is also known to be produced during traumatic events to nervous tissue. Alzheimer’s disease patients have reduced levels of IL-33, and, for this reason, researchers have proposed IL-33, or the lack of, as an indicator for the disease.
Another important target for research is a receptor known as TREM2 (Triggering Receptor Expressed On Myeloid Cells 2). TREM2 is expressed on glial cells and plays a role in the abnormal production of tau protein and amyloid-beta, two of the major causes of Alzheimer’s disease. In normal brains, tau protein provides support to the neuron’s internal transport systems. In Alzheimer’s brains, abnormal tau protein forms knots that clog the system known as neurofibrillary tangles. This disruption in intracellular transportation also impairs communication between neurons.
TREM2 receptors also take part in the signaling process that tells the glial cells to clear deposits of amyloid-beta. Interruptions in the normal function of TREM2 will lead to the accumulation of amyloid and other cellular debris. If left uncollected, the debris coalesce into plaques that increase inflammation and contribute to neurodegeneration. Researchers believe that modulating or controlling the expression of this receptor may provide a way to prevent the development of Alzheimer’s disease.
CBD’s role as a modulator of the inflammatory response to injury makes it an ideal candidate for research on Alzheimer’s disease. Previous research on receptor response to CBD in Alzheimer’s disease provided scientists with some insight on how CBD may influence the expression of receptors such as TREM2.
CBD Prevents Inflammation and Abnormal Protein Buildup
Khodadadi and colleagues recently published an article in The Journal of Alzheimer’s Disease where they tested whether CBD would improve outcomes for cognitive function in Alzheimer’s disease through regulating IL-33 and TREM2 receptors (4). For the study, the authors used genetically modified mice that carry human genes associated with Alzheimer’s disease. These mice develop the same abnormalities that lead to Alzheimer’s in humans, such as the buildup of amyloid plaque and the resulting neuroinflammatory changes that lead to the disease.
The researchers gave CBD to one group of mice and kept an untreated control group for comparison. Khodadadi and colleagues subjected these Alzheimer’s disease modeling mice to a series of cognition and behavioral tests to measure any effects CBD might have while the neuroinflammatory response progressed. The authors also took samples from the brain of the mice to examine the effects of CBD at the cellular level.
Treatment with CBD had a significant effect on several parameters. Cognitive function improved in the mice that received CBD, in contrast to the control group that showed a consistent decline. Examination of brain tissues from the treated mice showed reduced deposits of amyloid-beta. Regarding the inflammatory response, IL-33 was elevated in the CBD treated mice and so was the expression of the TREM2 receptor, compared to the untreated group. The mice that received CBD also had decreased levels of IL-6, a promoter of inflammation.
The authors believe that the effect of IL-33 over the “scavenging” of amyloid-beta contributed to the decreased amount of abnormal protein deposits. CBD elevated IL-33 and TREM2 expression while suppressing pro-inflammatory effects. This combined action prevented further neuronal damage and improved cognition in the mice while the neuroinflammatory response was taking place.
How Can We Best Treat Alzheimer’s Disease?
Current treatments for Alzheimer’s disease mitigate symptoms rather than treating the cause of the disease. CBD may present a disease-modifying alternative to attenuate cognitive decline and to prevent further neurodegeneration caused by the inflammatory response triggered by the disease. Khodadadi and colleagues conclude, “This intriguing finding and issues such as CBD dosing and type (e.g., isolate CBD versus full spectrum CBD) in Alzheimer’s disease treatment as well as the effects of sex-dimorphism, age, and the relationship with CBD treatment on outcomes of AD and other dementias warrants further exploration.”
- Hao F, Feng Y. Cannabidiol (CBD) enhanced the hippocampal immune response and autophagy of APP/PS1 Alzheimer's mice uncovered by RNA-seq. Life Sci. 2021;264:118624. doi:10.1016/j.lfs.2020.118624
- Páez JA, Campillo NE. Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer's Disease and Less Well-Known Diseases. Curr Med Chem. 2019;26(18):3300-3340. doi:10.2174/0929867325666180226095132
- Mulder J, Zilberter M, Pasquaré SJ, et al. Molecular reorganization of endocannabinoid signalling in Alzheimer's disease. Brain. 2011;134(Pt 4):1041-1060. doi:10.1093/brain/awr046
- Khodadadi H, Lopes Salles É, Jarrahi A, et al. Cannabidiol Ameliorates Cognitive Function via Regulation of IL-33 and TREM2 Upregulation in a Murine Model of Alzheimer's Disease [published online ahead of print, 2021 Feb 17]. J Alzheimers Dis. 2021;10.3233/JAD-210026. doi:10.3233/JAD-210026