Inhibition of Double-Stranded RNA-Dependent Protein Kinase Strongly Decreases Cytokine Production and Release in Peripheral Blood Mononuclear Cells from Patients with Alzheimer's Disease

Article type: Research Article

Authors: Couturier, Julien^a | Page, Guylène^{a; *} | Morel, Milena^a | Gontier, Céline^a | Lecron, Jean-Claude^{b; c} | Pontcharraud, Raymond^a | Fauconneau, Bernard^a | Paccalin, Marc^{a; d; e}

Affiliations: [a] Research Group on Brain Aging, GReViC EA 3808, University of Poitiers, Poitiers Cedex, France | [b] Laboratory Inflammation, Epithelial Tissues and Cytokines, EA 4331, University of Poitiers, Poitiers Cedex, France | [c] Department of Immunology-Inflammation, Poitiers University Hospital, Poitiers Cedex, France | [d] Department of Geriatrics, Poitiers University Hospital, Poitiers Cedex, France | [e] CIC, Poitiers University Hospital, Poitiers Cedex, France

Correspondence: [*] Correspondence to: Professor Guylène Page, PhD, Research Group on Brain Aging, GReViC EA 3808, University of Poitiers, 6 rue de la Milétrie, BP 199, 86034 Poitiers Cedex, France. Tel.: +33 549366260; Fax: +33 549366263; E-mail: [email protected].

Note: [] Handling Associate Editor: Marcella Reale

Abstract: Alzheimer's disease (AD), a neurodegenerative disorder, is the most common form of dementia in the elderly individuals. Among the pathogenic mechanisms in AD, chronic systemic inflammation is described and characterized by massive production of proinflammatory cytokines by peripheral blood mononuclear cells (PBMCs), which may contribute to an altered immune response and exacerbation of neurodegeneration. Studies have also reported increased double-stranded RNA-dependent protein kinase (PKR) activation in the PBMCs of patients with AD. Interestingly, PKR could be involved in NF-κB activation, leading to production of a wide range of cytokines. We proposed to decrease proinflammatory cytokines production and release by treating the PBMCs in 25 patients with AD with a specific inhibitor of PKR. Our results showed that PKR inhibition greatly decreased tumor necrosis factor α, interleukin (IL)-1α, IL-1β, and IL-6 production and release but did not affect the chemokine RANTES. Moreover, inhibition of the proinflammatory factors was correlated with prevention of caspase-3 activation. These results indicated that specific inhibition of PKR at the peripheral level might decrease the inflammatory response in AD.

Keywords: Alzheimer's disease, apoptosis, blood cells, chemokines, cytokines, NF-κB, protein kinase PKR

DOI: 10.3233/JAD-2010-100258

Journal: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1217-1231, 2010