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Mitochondrial Dysfunction and Immune Activation are Detectable in Early Alzheimer's Disease Blood

Article type: Research Article

Authors: Lunnon, Katiea; b; 1 | Ibrahim, Zinaa; b; 1 | Proitsi, Petroulaa; b | Lourdusamy, Anbarasua; b | Newhouse, Stephena; b | Sattlecker, Martinaa; b | Furney, Simona; b; 2 | Saleem, Muzamila; b | Soininen, Hilkkac | Kłoszewska, Iwonad | Mecocci, Patriziae | Tsolaki, Magdaf | Vellas, Brunog | Coppola, Giovannih | Geschwind, Danielh | Simmons, Andrewa; b | Lovestone, Simona; b | Dobson, Richarda; b; 1 | Hodges, Angelaa; b; 1; * | on behalf of the AddNeuroMed Consortium

Affiliations: [a] Institute of Psychiatry, King's Health Partners Centre for Neurodegeneration Research, King's College London, London, UK | [b] NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King's College London, London, UK | [c] Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland | [d] Medical University of Lodz, Lodz, Poland | [e] Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy | [f] 3rd Department of Neurology, “G. Papanicolaou” Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece | [g] INSERM U 558, University of Toulouse, Toulouse, France | [h] Department of Neurology, Programme in Neurogenetics, David Geffen School of Medicine, University of California at Los Angeles, CA, USA

Correspondence: [*] Correspondence to: Angela Hodges, King's College London, Institute of Psychiatry, De Crespigny Park, London, UK. Tel.: +44 207 848 0772; Fax: +44 207 848 0632; E-mail: [email protected].

Note: [1] These authors contributed equally to the work.

Note: [2] Present address: The Institute of Cancer Research, London, UK.

Keywords: Alzheimer's disease, blood, gene expression pattern analysis, inflammation, late onset, mild cognitive impairment, mitochondria

DOI: 10.3233/JAD-2012-111592

Journal: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 685-710, 2012

Accepted 25 February 2012
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Published: 4 June 2012
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Abstract

Alzheimer's disease (AD), like other dementias, is characterized by progressive neuronal loss and neuroinflammation in the brain. The peripheral leukocyte response occurring alongside these brain changes has not been extensively studied, but might inform therapeutic approaches and provide relevant disease biomarkers. Using microarrays, we assessed blood gene expression alterations occurring in people with AD and those with mild cognitive changes at increased risk of developing AD. Of the 2,908 differentially expressed probes identified between the three groups (p < 0.01), a quarter were altered in blood from mild cognitive impairment (MCI) and AD subjects, relative to controls, suggesting a peripheral response to pathology may occur very early. There was strong evidence for mitochondrial dysfunction with decreased expression of many of the respiratory complex I-V genes and subunits of the core mitochondrial ribosome complex. This mirrors changes previously observed in AD brain. A number of genes encoding cell adhesion molecules were increased, along with other immune-related genes. These changes are consistent with leukocyte activation and their increased the transition from circulation into the brain. In addition to expression changes, we also found increased numbers of basophils in people with MCI and AD, and increased monocytes in people with an AD diagnosis. Taken together this study provides both an insight into the functional response of circulating leukocytes during neurodegeneration and also identifies potential targets such as the respiratory chain for designing and monitoring future therapeutic interventions using blood.

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