Upregulation of glycolytic enzymes, mitochondrial dysfunction and increased cytotoxicity in glial cells treated with Alzheimer's disease plasma

Tharusha Jayasena; Anne Poljak; Nady Braidy; George Smythe; Mark Raftery; Mark Hill; Henry Brodaty; Julian Trollor; Nicole Kochan; Perminder Sachdev

doi:10.1371/journal.pone.0116092

Upregulation of glycolytic enzymes, mitochondrial dysfunction and increased cytotoxicity in glial cells treated with Alzheimer's disease plasma

PLoS One. 2015 Mar 18;10(3):e0116092. doi: 10.1371/journal.pone.0116092. eCollection 2015.

Authors

Tharusha Jayasena¹, Anne Poljak², Nady Braidy³, George Smythe⁴, Mark Raftery⁵, Mark Hill⁶, Henry Brodaty⁷, Julian Trollor⁸, Nicole Kochan⁸, Perminder Sachdev⁸

Affiliations

¹ Bioanalytical Mass Spectrometry Facility, MW Analytical Centre, University of New South Wales, Sydney, Australia; Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia.
² Bioanalytical Mass Spectrometry Facility, MW Analytical Centre, University of New South Wales, Sydney, Australia; Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia; School of Medical Sciences, University of New South Wales, Sydney, Australia.
³ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia.
⁴ Bioanalytical Mass Spectrometry Facility, MW Analytical Centre, University of New South Wales, Sydney, Australia; School of Medical Sciences, University of New South Wales, Sydney, Australia.
⁵ Bioanalytical Mass Spectrometry Facility, MW Analytical Centre, University of New South Wales, Sydney, Australia.
⁶ School of Medical Sciences, University of New South Wales, Sydney, Australia.
⁷ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia; Dementia Collaborative Research Centre, University of New South Wales, Sydney, Australia.
⁸ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia; Neuropsychiatric Institute, the Prince of Wales Hospital, Sydney, Australia.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder associated with increased oxidative stress and neuroinflammation. Markers of increased protein, lipid and nucleic acid oxidation and reduced activities of antioxidant enzymes have been reported in AD plasma. Amyloid plaques in the AD brain elicit a range of reactive inflammatory responses including complement activation and acute phase reactions, which may also be reflected in plasma. Previous studies have shown that human AD plasma may be cytotoxic to cultured cells. We investigated the effect of pooled plasma (n = 20 each) from healthy controls, individuals with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) on cultured microglial cells. AD plasma and was found to significantly decrease cell viability and increase glycolytic flux in microglia compared to plasma from healthy controls. This effect was prevented by the heat inactivation of complement. Proteomic methods and isobaric tags (iTRAQ) found the expression level of complement and other acute phase proteins to be altered in MCI and AD plasma and an upregulation of key enzymes involved in the glycolysis pathway in cells exposed to AD plasma. Altered expression levels of acute phase reactants in AD plasma may alter the energy metabolism of glia.

Publication types

Clinical Study
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease / blood*
Alzheimer Disease / pathology
Cell Line, Transformed
Female
Glycolysis*
Humans
Male
Mitochondria / enzymology*
Mitochondria / pathology
Neuroglia / enzymology*
Neuroglia / pathology
Plasma*

Grants and funding

This work was facilitated by the generous financial support of the Rebecca L Cooper Medical Research Foundation (http://www.cooperfoundation.org.au) and The University of New South Wales, Equity and Diversity Unit. This study is supported by the NHMRC Program Grants (ID 350833 and ID 568969) awarded to Professors Sachdev and Brodaty and Dr Trollor. None of the authors have any conflicts of interests with regard to this work. Mass spectrometry analyses were carried out at the Bioanalytical Mass Spectrometry Facility, UNSW, and was supported in part by grants from the Australian Government Systemic Infrastructure Initiative and Major National Research Facilities Program and by the UNSW Capital Grants Scheme (http://www.bmsf.unsw.edu.au/aboutus/funding.htm). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.