Microglia limit the expansion of beta-amyloid plaques in a mouse model of Alzheimer's disease

Background: Microglia are known as resident immune cells in the brain. beta-amyloid (A beta) plaques in the brain of Alzheimer's disease (AD) are surrounded by microglia, but whether and how microglia affect the formation and maintenance of plaques remains controversial. Methods: We depleted microglia by injecting diphtheria toxin (DT) in CX(3)CR1(CreER/+):R26(DTR/+) (CX(3)CR1-iDTR) mice crossed with APPswe/PSEN1dE9 (APP/PS1) mice. Intravital time-lapse imaging was performed to examine changes in the number and size of Congo Red-labeled amyloid plaques over 1-2 weeks. We also examined spine density and shaft diameter of dendrites passing through plaques in a PSAPP mouse model of AD (PS1(M146L) line 6.2 x Tg2576) crossed with Thy1 YFP H-line mice. Results: We found that DT administration to CX(3)CR1-iDTR mice efficiently ablated microglia within one week and that microglia repopulated in the second week after DT administration. Microglia depletion didn't affect the number of amyloid plaques, but led to similar to 13% increase in the size of A beta plaques within one week. Moreover, microglia repopulation was associated with the stabilization of plaque size during the second week. In addition, we found dendritic spine loss and shaft atrophy in the distal parts of dendrites passing through plaques. Conclusion: Our results demonstrate the important role of microglia in limiting the growth of A beta plaques and plaque-associated disruption of neuronal connection.