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Clearance of amyloid-? peptides by microglia and macrophages: the issue of what, when and where.

ABSTRACT: Accumulation of senile plaques consisting of amyloid-? peptide (A?) aggregates is a prominent pathological feature in Alzheimer's disease. Effective clearance of A? from the brain parenchyma is thought to regulate the development and progression of the disease. Macrophages in the brain play an important role in A? clearance by a variety of phagocytic and digestive mechanisms. Subpopulations of macrophages are heterogeneous such that resident microglia in the parenchyma, blood macrophages infiltrating from the periphery, and perivascular macrophages residing along cerebral vessels make functionally distinct contributions to A? clearance. Despite phenotypic similarities between the different macrophage subsets, a series of in vivo models have been derived to differentiate their relative impacts on A? dynamics as well as the molecular mechanisms underlying their activities. This review discusses the key findings from these models and recent research efforts to selectively enhance macrophage clearance of A?.

SUBMITTER: Lai AY

PROVIDER: S-EPMC3380064 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Clearance of amyloid-β peptides by microglia and macrophages: the issue of what, when and where.

Lai Aaron Y AY McLaurin Joanne J

Future neurology 20120301 2

Accumulation of senile plaques consisting of amyloid-β peptide (Aβ) aggregates is a prominent pathological feature in Alzheimer's disease. Effective clearance of Aβ from the brain parenchyma is thought to regulate the development and progression of the disease. Macrophages in the brain play an important role in Aβ clearance by a variety of phagocytic and digestive mechanisms. Subpopulations of macrophages are heterogeneous such that resident microglia in the parenchyma, blood macrophages infiltr ...[more]

PMID: 22737039

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Project description:BACKGROUND:Neuroinflammation is thought to contribute to the pathogenesis of Alzheimer's disease (AD), yet numerous studies have demonstrated a beneficial role for neuroinflammation in amyloid plaque clearance. We have previously shown that sustained expression of IL-1β in the hippocampus of APP/PS1 mice decreases amyloid plaque burden independent of recruited CCR2+ myeloid cells, suggesting resident microglia as the main phagocytic effectors of IL-1β-induced plaque clearance. To date, however, the mechanisms of IL-1β-induced plaque clearance remain poorly understood. METHODS:To determine whether microglia are involved in IL-1β-induced plaque clearance, APP/PS1 mice induced to express mature human IL-1β in the hippocampus via adenoviral transduction were treated with the Aβ fluorescent probe methoxy-X04 (MX04) and microglial internalization of fibrillar Aβ (fAβ) was analyzed by flow cytometry and immunohistochemistry. To assess microglial proliferation, APP/PS1 mice transduced with IL-1β or control were injected intraperitoneally with BrdU and hippocampal tissue was analyzed by flow cytometry. RNAseq analysis was conducted on microglia FACS sorted from the hippocampus of control or IL-1β-treated APP/PS1 mice. These microglia were also sorted based on MX04 labeling (MX04+ and MX04- microglia). RESULTS:Resident microglia (CD45loCD11b+) constituted > 70% of the MX04+ cells in both Phe- and IL-1β-treated conditions, and < 15% of MX04+ cells were recruited myeloid cells (CD45hiCD11b+). However, IL-1β treatment did not augment the percentage of MX04+ microglia nor the quantity of fAβ internalized by individual microglia. Instead, IL-1β increased the total number of MX04+ microglia in the hippocampus due to IL-1β-induced proliferation. In addition, transcriptomic analyses revealed that IL-1β treatment was associated with large-scale changes in the expression of genes related to immune responses, proliferation, and cytokine signaling. CONCLUSIONS:These studies show that IL-1β overexpression early in amyloid pathogenesis induces a change in the microglial gene expression profile and an expansion of microglial cells that facilitates Aβ plaque clearance.

Project description:Neuroinflammation is thought to contribute to the pathogenesis of Alzheimer’s disease (AD), yet numerous studies have demonstrated a beneficial role for neuroinflammation in amyloid plaque clearance. We have previously shown that sustained expression of IL-1β in the hippocampus of APP/PS1 mice decreases amyloid plaque burden independent of recruited CCR2+ myeloid cells, suggesting resident microglia as the main phagocytic effectors of IL-1β-induced plaque clearance. To date, however, the mechanisms of IL-1β-induced plaque clearance remain poorly understood. To determine whether IL-1β-induced plaque clearance is due to enhanced microglial phagocytosis of Aβ, APP/PS1 mice induced to express mature human IL-1β in the hippocampus via adenoviral transduction were treated with the Aβ fluorescent probe methoxy-X04 (MX04) and microglial internalization of Aβ was analyzed by flow cytometry and immunohistochemistry. We found that resident microglia (CD45loCD11b+) constituted >70% of the MX04+ cells in both control and IL-1β-treated conditions, and that <10% of MX04+ cells were recruited myeloid cells (CD45hiCD11b+). However, we found that IL-1β treatment did not augment the percentage of MX04+ microglia nor the quantity of Aβ internalized by individual microglia. Instead, we found that IL-1β treatment resulted in a significant increase in the total number of MX04+ microglia in the hippocampus due to IL-1β-induced proliferation. Consistent with these results, transcriptomic analyses revealed very similar gene expression profiles between MX04+ and MX04- microglia, indicating IL-1β does not drive enhanced expression of phagocytosis-related genes. By contrast, IL-1β treatment was associated with large-scale changes in the expression of genes related to proliferation, immune function and inflammation. Together, these studies demonstrate that IL-1β induces microglial proliferation and the expression of genes involved in inflammatory immune functions that may be related to Aβ clearance.

Dataset Information

Clearance of amyloid-? peptides by microglia and macrophages: the issue of what, when and where.

Publications

Clearance of amyloid-β peptides by microglia and macrophages: the issue of what, when and where.

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