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Innate phagocytosis by peripheral blood monocytes is altered in Alzheimer’s disease

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Abstract

Sporadic Alzheimer’s disease (AD) is characterised by the deposition and accumulation of specific protein aggregates. Failure of clearance could underlie this process, and recent genetic association studies point towards involvement of the phagocytosis and autophagy pathways. We developed a real-time tri-color flow cytometry method to quantitate the phagocytic function of human peripheral blood monocyte subsets including non-classic CD14dimCD16+, intermediate CD14+CD16+ and classic CD14+CD16− monocytes. Using this method, we have measured the phagocytic ability of fresh monocytes in a study of preclinical, prodromal and clinical AD, matched with cognitively normal healthy control subjects. Basal levels of phagocytosis in all three subsets of monocytes were similar between healthy controls and AD patients, while a significant increase of basal phagocytosis was found in subjects with high Aβ-amyloid burden as assessed by PET scans. Pre-treating cells with Copaxone (CPX, to stimulate phagocytosis) or ATP (an inhibitor of P2X7-mediated phagocytosis) showed a differential response depending on clinical or Aβ-burden status, indicating a relative functional deficit. Overall the results are consistent with a perturbation of basal and stimulated innate phagocytosis in sporadic AD.

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Abbreviations

CPX:

Copaxone (also known as glatiramer acetate)

AD:

Alzheimer’s disease

HC:

Healthy controls

MCI:

Mild cognitive impairment

SUVR:

Standardized uptake value ratio

NMMHC-IIA:

Nonmuscle myosin heavy chain IIA

FITC:

Fluorescein isothiocyanate

APC:

Allophycocyanin

mAb:

Monoclonal antibodies

YG:

Yellow–green

YO:

Yellow–orange

CytD:

Cytochalasin D

PBS:

Phosphate buffered saline

PBMCs:

Peripheral blood mononuclear cells

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Acknowledgments

We thank Dr. Verena Wimmer for the help of confocal microscopy. A full list of AIBL investigators can be found at http://aibl.csiro.au/about/aibl-research-team. This work was supported by ARC Future Fellowship (BG, FT120100581) and NHMRC Project Grant (1048082, 1061419), Macular Disease Foundation Australia Project Grant (2014-–2016), Macular Society Grant USA (2015) and the Victorian Government’s Operational Infrastructure Support Grant to the Florey Institute.

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Authors and Affiliations

  1. The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia

    Ben J. Gu, Xin Huang, Amber Ou, Alan Rembach, Christopher Fowler, Pavan K. Avula, Adam Horton, Victor L. Villemagne, Paul Maruff, James S. Wiley & Colin L. Masters

  2. CSIRO Health and Biosecurity/Australian E-Health Research Centre, Herston, QLD, 4029, Australia

    James D. Doecke

  3. Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, VIC, 3084, Australia

    Victor L. Villemagne

  4. CSIRO Health and Biosecurity, Parkville, VIC, 3052, Australia

    S. Lance Macaulay

  5. Cogstate Pty Ltd, Melbourne, VIC, 3000, Australia

    Paul Maruff

  6. Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, 3010, Australia

    Erica L. Fletcher

  7. Centre for Eye Research Australia Royal Victorian Eye and Ear Hospital, The University of Melbourne, East Melbourne, VIC, 3002, Australia

    Robyn Guymer

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  1. Ben J. Gu
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  2. Xin Huang
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  3. Amber Ou
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  4. Alan Rembach
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The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study

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Correspondence to Ben J. Gu.

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Deceased: Alan Rembach, 20 November 2014.

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Gu, B.J., Huang, X., Ou, A. et al. Innate phagocytosis by peripheral blood monocytes is altered in Alzheimer’s disease. Acta Neuropathol 132, 377–389 (2016). https://doi.org/10.1007/s00401-016-1596-3

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