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Chiara Maria Righini1, Larissa Estessi de Souza1, Jean Marques Brizola1
1University of São Paulo Medical School, São Paulo, São Paulo, Brazil.
Background:
Down Syndrome (DS) is considered a genetic form of Alzheimer's disease (AD) as it increases the expression of AD-related genes, leading to precocious neuroinflammation and cell death. Given the increasing longevity of the DS population, it is essential to look for alternatives to delay AD development and improve quality of life. Considering that physical exercise and cannabidiol (CBD) have recognized neuroprotective properties, the aim of this study was to evaluate the effects of these interventions alone and in combination, in a model of DS using positron emission tomography (PET).
Method:
Ts65Dn trisomic mice (ethical approval: 1292/2019, 1811/2022, 2065/2024) were divided into four groups: control (no treatment); exercise; CBD; and exercise+CBD. The exercise group was subjected to physical exercise on a treadmill from 2 to 8 months of age, 3 times/week, and the CBD group was treated at 7 months of age for 30 days (20 mg/kg, ip). The exercise+CBD group received both treatments as described above. PET images with [11C]PK11195 and [18F]FDG were acquired to assess brain metabolism and neuroinflammation at 4 and 8 months of age using a small animal PET scanner. The average standardized uptake value (SUV) was calculated considering the whole brain (WB) and the hippocampus.
Result:
At 4 months, exercise+CBD had higher [11C]PK11195 uptake in the WB and hippocampus compared to the other groups (control: p = 0.0006 in both; exercise: p = 0.009 and p = 0.005; CBD: p = 0.0007 and p = 0.0006). At 8 months, CBD and CBD+exercise had higher radiotracer uptake compared to the control (WB: p = 0.0005 and p = 0.0003, respectively; hippocampus: p = 0.0002 and p = 0.0003, respectively) and exercise groups (WB: p = 0.0009 and p = 0.0005, respectively; hippocampus: p <0.0001 for both). The CBD group showed increased [11C]PK11195 uptake in the WB (p <0.0001) and hippocampus (p <0.0001) at 8 months of age. Regarding [18F]FDG, the exercise+CBD group had an increase in uptake from 4 to 8 months in both regions (WB: p = 0.03; hippocampus: p = 0.04).
Conclusion:
Our data suggest that CBD treatment induced a higher glial response that was not present when CBD was associated with physical exercise. Indeed, this association increased brain metabolism, suggesting a neuroprotective mechanism.
Insights
Physical exercise combined with cannabidiol (CBD) shows neuroprotective effects in a Down Syndrome (DS) mouse model. This combination enhanced brain metabolism, suggesting a potential strategy to delay Alzheimer's disease (AD) development in DS individuals.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Down Syndrome (DS) is linked to early-onset Alzheimer's disease (AD) due to increased expression of AD-related genes, causing neuroinflammation and cell death.
- The growing lifespan of the DS population necessitates strategies to delay AD progression and enhance quality of life.
- Physical exercise and cannabidiol (CBD) are known for their neuroprotective properties.
Purpose of the Study:
- To investigate the effects of physical exercise and CBD, individually and in combination, on a mouse model of Down Syndrome (DS).
- To assess neuroinflammation and brain metabolism using positron emission tomography (PET) in DS mice under different treatment conditions.
Main Methods:
- Ts65Dn trisomic mice were divided into four groups: control, exercise, CBD, and exercise+CBD.
- Exercise involved treadmill activity three times weekly from 2 to 8 months of age.
- CBD was administered intraperitoneally (20 mg/kg) for 30 days starting at 7 months of age.
- PET imaging ([11C]PK11195 and [18F]FDG) was used to evaluate neuroinflammation and brain metabolism at 4 and 8 months of age.
Main Results:
- At 4 months, the exercise+CBD group showed significantly higher [11C]PK11195 uptake (neuroinflammation marker) in the whole brain (WB) and hippocampus compared to other groups.
- At 8 months, both CBD and exercise+CBD groups exhibited increased [11C]PK11195 uptake compared to control and exercise groups.
- The exercise+CBD group demonstrated increased [18F]FDG uptake (brain metabolism) from 4 to 8 months in both WB and hippocampus.
Conclusions:
- CBD treatment alone induced a notable glial response, which was modulated when combined with physical exercise.
- The combination of exercise and CBD enhanced brain metabolism, suggesting a potential neuroprotective mechanism against AD development in DS.
- This combined approach may offer a promising strategy for improving brain health in individuals with Down Syndrome.
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