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Young microglia restore amyloid plaque clearance of aged microglia.

ABSTRACT: Alzheimer's disease (AD) is characterized by deposition of amyloid plaques, neurofibrillary tangles, and neuroinflammation. In order to study microglial contribution to amyloid plaque phagocytosis, we developed a novel ex vivo model by co-culturing organotypic brain slices from up to 20-month-old, amyloid-bearing AD mouse model (APPPS1) and young, neonatal wild-type (WT) mice. Surprisingly, co-culturing resulted in proliferation, recruitment, and clustering of old microglial cells around amyloid plaques and clearance of the plaque halo. Depletion of either old or young microglial cells prevented amyloid plaque clearance, indicating a synergistic effect of both populations. Exposing old microglial cells to conditioned media of young microglia or addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was sufficient to induce microglial proliferation and reduce amyloid plaque size. Our data suggest that microglial dysfunction in AD may be reversible and their phagocytic ability can be modulated to limit amyloid accumulation. This novel ex vivo model provides a valuable system for identification, screening, and testing of compounds aimed to therapeutically reinforce microglial phagocytosis.

SUBMITTER: Daria A

PROVIDER: S-EPMC5331757 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Young microglia restore amyloid plaque clearance of aged microglia.

Daria Anna A Colombo Alessio A Llovera Gemma G Hampel Heike H Willem Michael M Liesz Arthur A Haass Christian C Tahirovic Sabina S

The EMBO journal 20161221 5

Alzheimer's disease (AD) is characterized by deposition of amyloid plaques, neurofibrillary tangles, and neuroinflammation. In order to study microglial contribution to amyloid plaque phagocytosis, we developed a novel <i>ex vivo</i> model by co-culturing organotypic brain slices from up to 20-month-old, amyloid-bearing AD mouse model (APPPS1) and young, neonatal wild-type (WT) mice. Surprisingly, co-culturing resulted in proliferation, recruitment, and clustering of old microglial cells around ...[more]

PMID: 28007893

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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.

Project description:Triggering receptor expressed on myeloid cells 2 (TREM2) plays a crucial role in regulating microglial functions and removal of amyloid plaques in Alzheimer's disease (AD). However, therapeutics based on this knowledge have not been developed due to the low antibody brain penetration and weak TREM2 activation. In this study, we engineered a TREM2 bispecific antibody to potently activate TREM2 and enter the brain. To boost TREM2 activation, we increased the valency of bivalent anti-TREM2 Ab2 IgG to tetra-variable domain immunoglobulin (TVD-Ig), thus improving the EC50 of amyloid-β oligomer (oAβ)-lipid microglial phagocytosis by more than 100-fold. Ab2 TVD-Ig treatment also augmented both microglia migration toward oAβ and microglia survival by 100-fold over the bivalent IgG antibody. By targeting the transferrin receptor (TfR), the brain-penetrating Ab2 TVD-Ig/αTfR bispecific antibody realized broad brain parenchyma distribution with a 10-fold increase in brain antibody concentration. Ab2 TVD-Ig/αTfR treatment of 5-month-old 5XFAD mice significantly boosted microglia-plaque interactions and enhanced amyloid plaque phagocytosis by microglia. Thus, potent TREM2 activation by a multivalent agonist antibody coupled with TfR-mediated brain entry can boost microglia clearance of amyloid plaques, which suggests the antibody has potential as an AD treatment.List of abbreviations AD: Alzheimer's disease; Ab: antibody; APOE: apolipoprotein E; Aβ: amyloid beta; BBB: blood-brain barrier; BLI: bio-layer interferometry; CNS: central nervous system; CSF: colony-stimulating factor; CytoD: cytochalasin d; DAM: microglia type associated with neurodegenerative diseases; DAP12: DNAX-activation protein 12; TVD-Ig: tetra-variable domain immunoglobulin; ECD: extracellular domain; ELISA: enzyme-linked immunoassay; ESC: embryonic stem cell; hMGLs: human embryonic stem cell-derived microglia-like lines; IBA1: ionized calcium-binding adaptor molecule 1; ITAM: immunoreceptor tyrosine-based activation motif; KiH: knob-into-hole; NFAT: nuclear factor of activated t-cells; PC: phosphatidylcholine; PK: pharmacokinetics; PS: phosphatidylserine; pSYK: phosphorylated spleen tyrosine kinase; scFv: single-chain variable fragment; SEC: size-exclusion chromatography; sTREM2: soluble triggering receptor expressed on myeloid cells 2; SYK: spleen tyrosine kinase; TfR: transferrin receptor; TREM2: triggering receptor expressed on myeloid cells 2.

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Young microglia restore amyloid plaque clearance of aged microglia.

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Young microglia restore amyloid plaque clearance of aged microglia.

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