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Microglia actions in Alzheimer’s disease

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Abstract

The identification of microglia-associated, neurological disease-causing mutations in patients, combined with studies in mouse models has highlighted microglia, the brain’s intrinsic myeloid cells, as key modulators of pathogenesis and disease progression in neurodegenerative diseases. In Alzheimer’s disease (AD) in particular, the activation and accumulation of microglial cells around β-Amyloid (Aβ) plaques has long been described and is believed to result in chronic neuroinflammation—a term that, despite being commonly used, lacks a precise definition. This seemingly directed response of microglia to amyloid deposits conflicts with the fact that the increasing buildup of Aβ plaques is not inhibited by these cells during disease progression. While recent evidence suggests that microglia lose their intrinsic beneficial function during the course of AD and may even acquire a “toxic” phenotype over time, Aβ may also simply not be an appropriate trigger to induce phagocytosis and degradation by microglia in vivo. As recent experimental evidence has indicated the importance of the microglia in AD pathogenesis, future efforts aimed at tackling this disease via utilization or modulation of microglia or factors therefrom appear to be an exciting and challenging research front.

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Abbreviations

Aβ:

Amyloid-β

sAβ:

Soluble Amyloid-β

AD:

Alzheimer’s disease

BM–MNC:

Bone marrow mononuclear cells

CCR2:

C-C chemokine receptor type 2

CD:

Cluster of differentiation

CNS:

Central nervous system

CSFR1:

Colony stimulating factor 1 receptor

CX3CR1:

CX3C chemokine receptor 1

CX3CL1:

Chemokine (C-X3-C motif) ligand 1 (Fraktalkine)

GWAS:

Genome wide association study

HDLS:

Hereditary diffuse leukoencephalopathy with spheroids

HLA:

Human leucocyte antigen

HSVTK:

Herpes-simplex virus thymidine kinase

IL:

Interleukin

LOAD:

Late-onset Alzheimer’s disease

LPS:

Lipopolysaccharide

MCP1:

Monocyte chemoattractant protein 1

M-CSF:

Macrophage colony-stimulating factor

MHC:

Major histocompatibility complex

MIP:

Macrophage inflammatory protein

MPL:

Monophosphoryl lipid A

NALP3:

NACHT, LRR and PYD domains-containing protein 3

NSAIDS:

Nonsteroidal anti-inflammatory drugs

RAGE:

Receptor for advanced glycation end products

TREM2:

Triggering receptor expressed on myeloid cells 2

TNF:

Tumor necrosis factor

TGF:

Transforming growth factor

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Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft (SFB TRR 43 to F.L.H. and S.P., and NeuroCure Exc 257 to F.L.H.), the US National Institutes of Health (NINDS R01 NS046006 to F.L.H.), and the Federal Ministry of Education and Research (BMBF; Kompetenznetz Degenerative Demenzen to S.P. and F.L.H.). We thank Wolfgang J. Streit, University of Florida, Gainesville, for image Fig. 3.

Conflict of interest

F.L.H holds a patent application by the Charité–Universitätsmedizin Berlin entitled “Modulators of IL-12 and/or IL-23 for the Prevention or Treatment of Alzheimer’s Disease” (PCT/EP2012/050066).

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  1. Department of Neuropathology, Charité, Universitätsmedizin Berlin, 10117, Berlin, Germany

    Stefan Prokop, Kelly R. Miller & Frank L. Heppner

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Prokop, S., Miller, K.R. & Heppner, F.L. Microglia actions in Alzheimer’s disease. Acta Neuropathol 126, 461–477 (2013). https://doi.org/10.1007/s00401-013-1182-x

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