CCR5 deficiency: decreased neuronal resilience to oxidative stress and increased risk of vascular dementia

Abstract Introduction As the chemokine receptor5 (CCR5) may play a role in ischemia, we studied the links between CCR5 deficiency, the sensitivity of neurons to oxidative stress, and the development of dementia. Methods Logistic regression models with CCR5 and ApoE polymorphisms were applied to 205 cognitively normal and 189 dementia patients included in Geneva. The impact of oxidative stress on Ccr5 expression and cell death was assessed in mice neurons. Results CCR5-Δ32 allele synergized with ApoEε4 as risk factor for dementia and specifically for dementia with a vascular component. We confirmed these results in an independent cohort from Italy (157 cognitively normal and 620 dementia). Carriers of the ApoEε4/CCR5-Δ32 genotype aged ≥80 years have an eleven-fold greater risk of vascular and mixed dementia. Oxidative stress induced cell death in Ccr5 -/- mice neurons. Discussion We propose the vulnerability of CCR5-deficient neurons in response to oxidative stress as possible mechanisms contributing to dementia.