Microglia contributes to plaque growth by cell death due to uptake of amyloid β in the brain of Alzheimer's disease mouse model

Abstract

Pathological hallmarks of Alzheimer's disease (AD) include extracellularly accumulated amyloid β (Aβ) plaques and intracellular neurofibrillary tangles in the brain. Activated microglia, brain-resident macrophages, are also found surrounding Aβ plaques. The study of the brain of AD mouse models revealed that Aβ plaque formation is completed by the consolidation of newly generated plaque clusters in vicinity of existed plaques. However, the dynamics of Aβ plaque formation, growth and the mechanisms by which microglia contribute to Aβ plaque formation are unknown. In the present study, we confirmed how microglia are involved in Aβ plaque formation and their growth in the brain of 5XFAD mice, the Aβ-overexpressing AD transgenic mouse model, and performed serial intravital two-photon microscopy (TPM) imaging of the brains of 5XFAD mice crossed with macrophage/microglia-specific GFP-expressing CX3CR1 mice. We found that activated microglia surrounding Aβ plaques take up Aβ, which are clusters developed inside activated microglia in vivo and this was followed by microglial cell death. These dying microglia release the accumulated Aβ into the extracellular space, which contributes to Aβ plaque growth. This process was confirmed by live TPM in vivo imaging and flow cytometry. These results suggest that activated microglia can contribute to formation and growth of Aβ plaques by causing microglial cell death in the brain. GLIA 2016;64:2274-2290.

Inflammatory mechanisms in neurodegeneration

“…Similarly, a two‐photon in vivo study indicated that microglial uptake of aggregated Aβ, followed by microglial death and release of residual Aβ, could lead to the spreading of amyloid deposition (Baik et al . ).…”

CD11a expression distinguishes infiltrating myeloid cells from plaque‐associated microglia in Alzheimer's disease

“…To overcome the limitations of these markers, lineage tracing mouse models have been generated using the microglial expression of the fractalkine receptor, Cx3cr1 (Jung et al, ). One study crossbred the Cx3cr1 GFP/GFP mice with the 5xFAD mouse model of AD and found that dying GFP positive cells contributed to Aβ plaque growth by releasing previously phagocytosed Aβ into the extracellular space (Baik, Kang, Son, & Mook Jung, ). However, macrophages can also express Cx3cr1, thus the contribution of peripheral monocyte‐derived macrophages cannot be ruled out.…”

Systemic immune‐checkpoint blockade with anti‐PD1 antibodies does not alter cerebral amyloid‐β burden in several amyloid transgenic mouse models

“…Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular deposits of amyloid‐β (Aβ) peptides, intracellular neurofibrillary tangles, and chronic neuroinflammation resulting in a progressive loss of memory and cognitive function (Prinz & Priller, ). While Aβ can be cleared by resident microglia and astrocytes (Baik et al, ; Ries & Sastre, ), these cells become unable to clear Aβ pathology as animals age. The peripheral immune system is clearly implicated in AD pathogenesis (Heneka et al, ; Prinz & Priller, ).…”