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Published on: June 17, 2015
Infiltrating Hematogenous Macrophages Aggregate Around β-Amyloid Plaques in an Age- and Sex-Dependent Manner in a
Natalie Kozyrev1, Shawn Albers1,2, Jennifer Yang3
1Molecular Medicine Research Laboratories, Robarts Research Institute, Western University, London, Ontario.
Abstract:
β-Amyloid (Aβ) plaques can trigger chronic inflammation in the cellular environment that recruits infiltrating macrophages during the course of Alzheimer disease (AD). Activated macrophages release pro-inflammatory cytokines that increase neurotoxicity associated with AD. A major impediment to investigating neuroinflammation involving macrophage activity is the inability to discriminate resident microglial macrophages (mMϕ) from hematogenous macrophages (hMϕ), as they are morphologically and phenotypically similar when activated. To distinguish between mMϕ and hMϕ and to determine their respective roles in chronic inflammation associated with the progression of amyloidosis, we used lys-EGFP-ki transgenic mice that express enhanced green fluorescent protein in hMϕ, but not in mMϕ. These mice were crossed with 5XFAD mice. The offspring demonstrated robust AD pathology and enabled visual discrimination of mMϕ from hMϕ. Mutant mice demonstrated robust increases in Aβ1-42, area of Aβ plaques, gliosis and deficits in spatial learning by age 5 months. The time-course of Aβ accumulation, paralleled by the accumulation of hMϕ around Aβ plaques, was more robust in female compared with male mice and preceded behavioral changes. Thus, the accumulation of infiltrating hMϕ around Aβ plaques was age- and sex-dependent and preceded cognitive impairment.
Insights
Hematogenous macrophages infiltrate the brain during Alzheimer disease (AD), contributing to neuroinflammation. Their accumulation around amyloid plaques is age- and sex-dependent and precedes cognitive decline.
Area of Science:
- Neuroscience
- Immunology
- Alzheimer Disease Research
Background:
- Alzheimer disease (AD) involves chronic neuroinflammation triggered by beta-amyloid (Aβ) plaques.
- Activated macrophages, both resident microglial (mMϕ) and infiltrating hematogenous (hMϕ), contribute to AD neurotoxicity.
- Distinguishing mMϕ from hMϕ is challenging due to similar activated phenotypes, hindering research on their specific roles.
Purpose of the Study:
- To differentiate between resident microglial macrophages (mMϕ) and hematogenous macrophages (hMϕ) in Alzheimer disease models.
- To investigate the distinct roles of mMϕ and hMϕ in chronic inflammation during amyloidosis progression.
- To establish a model for visualizing and quantifying macrophage infiltration in AD pathology.
Main Methods:
- Utilized lys-EGFP-ki transgenic mice, where hematogenous macrophages (hMϕ) express enhanced green fluorescent protein (EGFP).
- Crossed lys-EGFP-ki mice with 5XFAD transgenic mice, which exhibit robust Alzheimer disease pathology.
- Analyzed Aβ accumulation, plaque load, gliosis, spatial learning deficits, and macrophage infiltration in the resulting offspring.
Main Results:
- The crossed mouse model displayed significant AD pathology, including increased Aβ1-42, plaque area, and gliosis by 5 months of age.
- Hematogenous macrophages (hMϕ) were observed to accumulate around Aβ plaques, with this accumulation being more pronounced in female mice.
- The infiltration of hMϕ preceded the onset of spatial learning deficits, indicating a role in early AD progression.
Conclusions:
- Hematogenous macrophages (hMϕ) infiltrate the brain and accumulate around amyloid plaques in an age- and sex-dependent manner.
- The accumulation of infiltrating hMϕ precedes cognitive impairment in this Alzheimer disease model.
- This study provides a valuable tool for discriminating between resident and infiltrating macrophages, facilitating further research into neuroinflammation in AD.
