Summary: A two‑week, high‑dose course of cannabidiol (CBD) restored the function and levels of two proteins that help clear amyloid‑beta, and reduced inflammatory IL‑6, improving cognition in a mouse model of familial Alzheimer’s disease.
Source: Dental College of Georgia
Two weeks of high‑dose CBD restored critical immune‑related proteins involved in clearing beta‑amyloid plaque and improved behavioral measures of cognition and movement in a mouse model of early‑onset familial Alzheimer’s disease, researchers report.
The study focused on two proteins, TREM2 and IL‑33, which support microglial phagocytosis—the process by which the brain’s resident immune cells remove dead cells and extracellular debris, including amyloid‑beta. Levels of both proteins decline in Alzheimer’s disease, undermining the brain’s natural clean‑up processes.
In this preclinical study, investigators found that CBD normalized the expression and activity of IL‑33 and TREM2, reduced levels of the pro‑inflammatory cytokine IL‑6, and produced measurable improvements in cognition and motor behavior. The work, led by immunologist Dr. Babak Baban of the Dental College of Georgia, is published in the Journal of Alzheimer’s Disease.
“Current Alzheimer’s medications treat symptoms by enhancing neurotransmitter signaling but do not directly correct disease mechanisms,” says Dr. John Morgan, a neurologist and coauthor. The team therefore examined whether CBD could target underlying immune and clearance pathways that contribute to amyloid accumulation and neuroinflammation.
IL‑33 is primarily expressed in the brain in humans and acts as an alert signal when tissue damage or harmful aggregates are present. Emerging evidence also supports a context‑dependent regulatory role for IL‑33, where it can either amplify or restrain immune activity depending on the environment. In Alzheimer’s disease, IL‑33 appears to help reduce sustained inflammation and rebalance immune responses.
TREM2 is a receptor on microglia that, together with co‑receptors, transmits activation signals that support phagocytosis and other defensive actions. Reduced TREM2 expression or rare TREM2 gene variants are linked to increased Alzheimer’s risk. In the mouse model used here (5xFAD), both IL‑33 and TREM2 were low at baseline.
After CBD treatment, IL‑33 increased roughly sevenfold and TREM2 about tenfold in treated animals. Those molecular changes corresponded with behavioral improvements: mice recovered the ability to distinguish novel from familiar objects and stopped repetitive circling behavior that models movement impairment seen in some people with Alzheimer’s.
The investigators also measured IL‑6, a cytokine associated with chronic inflammation in Alzheimer’s patients, and observed reductions following CBD treatment. These combined effects — boosting clearance‑related proteins while lowering inflammatory signaling — suggest CBD may act on multiple interacting pathways that contribute to disease progression.
For this study, mice received high doses of CBD administered intraperitoneally every other day for two weeks during later stages of pathology. The research team reports that the same dosing regimen had previously been effective in reducing the severe inflammatory “cytokine storm” that contributes to acute respiratory distress syndrome (ARDS).
Next steps include defining optimal dosing, evaluating earlier intervention, and testing alternative delivery systems. The team is now administering CBD at the first signs of cognitive decline in the model and exploring inhaler‑based delivery to improve central nervous system targeting. A company has developed inhalers for both animal and human studies to support these efforts.
The study authors emphasize that familial Alzheimer’s is an inherited form that typically appears in patients in their 30s and 40s and represents about 10–15% of cases. They expect CBD could be at least as effective in more common sporadic forms of Alzheimer’s, which may present additional targets for the compound. Ongoing work includes testing CBD in models of nonfamilial Alzheimer’s and planning translational steps toward clinical trials.
Plaques of amyloid‑beta and neurofibrillary tangles of tau protein are the core pathological features of Alzheimer’s. Beta‑amyloid can accumulate in the brain many years before clinical dementia, and the later emergence of tau tangles more closely correlates with symptomatic decline. Modulating immune clearance and inflammation, the authors note, could influence this sequence and slow disease progression.
Other coauthors include Drs. David Hess, Kumar Vaibhav, and Krishnan Dhandapani. Funding for the research was provided by the National Institutes of Health.
About this Alzheimer’s disease research news
Source: Dental College of Georgia
Contact: Toni Baker – Dental College of Georgia
Image: The image is in the public domain
Original Research: “Cannabidiol Ameliorates Cognitive Function via Regulation of IL‑33 and TREM2 Upregulation in a Murine Model of Alzheimer’s Disease” by John Morgan et al., Journal of Alzheimer’s Disease. (Closed access)
Abstract
Cannabidiol Ameliorates Cognitive Function via Regulation of IL‑33 and TREM2 Upregulation in a Murine Model of Alzheimer’s Disease
There is an urgent need for innovative therapies that address the underlying mechanisms of Alzheimer’s disease. In this study, researchers evaluated whether cannabidiol (CBD) improves outcomes in a translational mouse model of familial Alzheimer’s disease and whether CBD regulates interleukin‑33 (IL‑33) and triggering receptor expressed on myeloid cells 2 (TREM2), both linked to cognitive resilience.
Using 5xFAD mice that model early‑onset familial Alzheimer’s, investigators applied behavioral tests and immunoassays to assess cognitive, motor, and molecular outcomes. The findings indicate that CBD treatment increased IL‑33 and TREM2 expression, reduced inflammatory IL‑6, ameliorated disease‑related behaviors, and slowed cognitive decline in this preclinical model.