Figure 9

Treatment with lentivirus expressing the CCR2 gene in the bone marrow rescues spatial memory in 6-month-old APP_Swe/PS1 and APP_Swe/PS1/CCR2⁻ mice. Three-month-old APP_Swe/PS1 and APP_Swe/PS1/CCR2⁻ mice received intrafemoral injections of a lentiviral construction containing GFP or GFP with a CCR2 transgene. At 6 months of age, mice were submitted to the water T-maze task. The number of trials to reach the criterion (A, B) and the time to arrive at the platform (C, D) were determined during the acquisition (A, C) and the reversal learning phases (B, D). Lenti-GFP-CCR2 treatment significantly decreased the number of trials and the time necessary to learn the platform position in APP_Swe/PS1/CCR2⁻ mice, as well as in APP_Swe/PS1 mice. Interestingly, lenti-GFP-CCR2-treated mice had performances similar to WT mice. Results are expressed as the mean ± SEM; n = 6−13; **P < 0.01 and ***P < 0.001 versus no treatment; ^##P < 0.01 versus lenti-GFP Two-way ANOVA was performed and revealed no interaction between the various genotypes and treatments. Bonferroni or Tamhane tests were used for post hoc comparisons. Blood cells were analyzed by FACS, and GFP expression was detected in leukocytes 2 and 3 months after lenti-GFP or lenti-GFP-CCR2 intrafemoral injection (E). Among the various leukocyte populations, GFP protein was preferentially expressed in monocytes. Results are expressed as the mean ± SEM; n = 4−6. BMCs transduced with lenti-CCR2 infiltrated the brain parenchyma of nonirradiated APP_Swe/PS1/CCR2^−/− mice, as depicted by confocal photomicrographs of the cerebral cortex (F, G) and hippocampus (H). Scale bar 10 µm. A-D: ■, No treatment; □, lenti-GFP; , lenti-GFP-CCR2; E: □, total cells; , lymphocytes; ■, monocytes; granulocytes.