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

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/apolipoprotein E (ApoE) polymorphisms were applied on a sample of 205 cognitively normal individuals and 189 dementia patients from 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 11‐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. [ABSTRACT FROM AUTHOR]