Abstract
BackgroundMicroglia are known as resident immune cells in the brain. β-amyloid (Aβ) 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.MethodsWe depleted microglia by injecting diphtheria toxin (DT) in CX3CR1CreER/+:R26DTR/+ (CX3CR1-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 (PS1M146L line 6.2 × Tg2576) crossed with Thy1 YFP H-line mice.ResultsWe found that DT administration to CX3CR1-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 ~13% increase in the size of Aβ 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.ConclusionOur results demonstrate the important role of microglia in limiting the growth of Aβ plaques and plaque-associated disruption of neuronal connection.
Highlights
Microglia are known as resident immune cells in the brain. β-amyloid (Aβ) 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
Our results suggest that microglia play an important role in limiting the growth of Aβ plaques and reducing neuronal damage associated with Aβ deposition
CX3CR1CreER mice were generated in New York University School of Medicine [40]. These mice were crossbred and litters were genotyped by PCR using the following primers: for APP/PS1 mice, 5′- TCATGACTATCCT CCTGGTGG-3′ and 5′- CGTTATAGGTTTTAA ACACTTCCCC-3′; for CX3CR1CreER mice, 5′- AAGAC TCACGTGGACCTGCT-3′, 5′- CGGTTATTCAACTT GCACCA-3′ and 5′- AGGATGTTG ACTTCCG AGTTG-3′; for diphtheria toxin receptor (DTR) mice, 5′- CTGGCTTCTGAGGACCG-3′ and 5′-CGAAGAGTTTGTCCTCAACCG-3′. 12–24 months old quadruple transgenic mice were used for microglia depletion experiment and in vivo imaging
Summary
Microglia are known as resident immune cells in the brain. β-amyloid (Aβ) 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. Studies in AD mouse models have shown that Aβ deposition is associated with various neuronal abnormalities, including the formation of dystrophic neurites [5, 7, 8], dendritic spine loss [5, 7, 9, 10], synaptic dysfunction [11, 12] and abnormal neuronal firing [13, 14]. Microglia are the resident immune cells in the central nervous system [20, 21] They are clustered around amyloid plaques in both human AD brains [22, 23] and the brains of AD mouse models [24, 25]. Microglia processes enveloping plaque surface are suggested to constitute a barrier to prevent plaque expansion [36, 37], and the disruption of this barrier in TREM2 deficiency mice is associated with the increase of
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