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Updated: Jan 11, 2026
In Vitro Modeling of Down Syndrome Neurogenesis Using Human-Induced Pluripotent Stem Cells
Published on: March 7, 2025
Targeting dysregulated CB1 receptors in a Down syndrome mouse model improves neurological outcomes
Anna Vázquez-Oliver1, Silvia Pérez-García1, Rafael Romero-Pérez1
1Laboratory of Neuropharmacology-NeuroPhar, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
Introduction:
Down syndrome (DS) is the most common genetic cause of intellectual disability, affecting cognitive function and increasing the risk of early-onset Alzheimer's disease (AD). The endocannabinoid system may serve as a therapeutic target for cognitive deficits by inhibiting cannabinoid type-1 receptor (CB1R) function.
Methods:
CB1R expression was analyzed in the hippocampi of aged DS-associated AD (DSAD) individuals and middle-aged Ts65Dn mice. Long-term oral treatment with the CB1R antagonist rimonabant was used to assess its effects on memory and neuroinflammation in the Ts65Dn mouse model of DS.
Results:
CB1R expression was significantly increased in both aged DSAD subjects (specifically in the dentate gyrus and CA2 posterior hippocampal subregions) and Ts65Dn mice. Long-term rimonabant treatment improved memory performance, normalized microglial morphology, and reduced plasma inflammatory markers in trisomic mice without preventing neuron decline.
Discussion:
These findings suggest that sustained CB1R inhibition may enhance cognitive function by modulating neuroinflammation, highlighting its therapeutic potential for cognitive impairments in DS.
Highlights:
Cannabinoid type-1 receptor (CB1R) expression is increased in the posterior hippocampus of aged Down syndrome (DS) subjects and Ts65Dn mice. Long-term rimonabant treatment enhances memory in middle-aged Ts65Dn mice. CB1R inhibition shifts neuroinflammatory features in Ts65Dn mice. CB1R inhibition does not halt noradrenergic/cholinergic neurodegeneration in Ts65Dn. CB1R inhibition presents potential for memory improvement in DS-related deficits.
