Increased inflammatory response in cytomegalovirus seropositive patients with Alzheimer's disease.

Gabriel Westman,David Berglund,Olle Korsgren,Martin Ingelsson,Johan Widén,Anna-Karin Lidehall,Lars Lannfelt,Britt-Marie Eriksson,Dag Sehlin,Thomas Arendt

doi:10.1371/journal.pone.0096779

Abstract

Alzheimer’s disease (AD) has been associated with increased local inflammation in the affected brain regions, and in some studies also with elevated levels of proinflammatory cytokines in peripheral blood. Cytomegalovirus (CMV) is known to promote a more effector-oriented phenotype in the T-cell compartment, increasing with age. The aim of this study was to investigate the inflammatory response of peripheral blood mononuclear cells (PBMCs) from AD patients and non-demented (ND) controls. Using a multiplex Luminex xMAP assay targeting GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10 and TNF-α, cytokine profiles from PBMCs were analysed after stimulation with anti-CD3/CD28 beads, CMV pp65 peptide mix or amyloid β (Aβ) protofibrils, respectively. CMV seropositive AD subjects presented with higher IFN-γ levels after anti-CD3/CD28 and CMV pp65 but not after Aβ stimulation, compared to CMV seropositive ND controls. When analysing IFN-γ response to anti-CD3/CD28 stimulation on a subgroup level, CMV seropositive AD subjects presented with higher levels compared to both CMV seronegative AD and CMV seropositive ND subjects. Taken together, our data from patients with clinically manifest AD suggest a possible role of CMV as an inflammatory promoter in AD immunology. Further studies of AD patients at earlier stages of disease, could provide better insight into the pathophysiology.

Highlights

Alzheimer’s disease (AD) is, besides the well-described neuropathologic changes with extracellular plaques of amyloid-b (Ab) and intracellular neurofibrillary tangles (NFT) of tau, characterised by a state of local inflammation in the affected brain regions [1,2]
AD subjects presented with similar baseline cytokine levels as ND controls, but showed a higher IFN-c response upon stimulation with both anti-CD3/CD28 Dynabeads and CMV pp65
AD subjects showed a stronger IFN-c response to both anti-CD3/ CD28 and CMV pp65 compared to ND subjects, which we believe is the result of a more inflammation-prone T-cell phenotype that could affect levels of inflammation in specific organs without producing significantly higher levels of inflammatory biomarkers in peripheral blood

Summary

Introduction

Alzheimer’s disease (AD) is, besides the well-described neuropathologic changes with extracellular plaques of amyloid-b (Ab) and intracellular neurofibrillary tangles (NFT) of tau, characterised by a state of local inflammation in the affected brain regions [1,2]. Elevated peripheral levels of proinflammatory cytokines in AD subjects have been found in some studies but not in others [3]. Offspring with a parental history of AD present with a more proinflammatory cytokine profile than those without [4] and patients with AD seem to deteriorate in cognitive capacity when challenged with inflammatory events [5]. The most common form of AD, sporadic late-onset disease, has multiple genetic, vascular and psychosocial risk factors with the ApoE e4 genotype being the strongest known genetic predictor [6,7]. It is not completely clear how these factors interact with Ab in the pathogenesis. There is increasing evidence that large soluble pre-fibrillar forms of Ab, so-called protofibrils, are more neurotoxic than monomers [9,10]

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