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Proteinase-Activated Receptor-2 Exerts Protective and Pathogenic Cell Type-Specific Effects in Alzheimer’s Disease¹

Amir Afkhami-Goli^*,,**,, Farshid Noorbakhsh^*,, Avril J. Keller, Nathalie Vergnolle, David Westaway^¶,||,#, Jack H. Jhamandas^*, Patricia Andrade-Gordon^*, Morley D. Hollenberg, Hosseinali Arab^**, Richard H. Dyck and Christopher Power^2,*,

^* Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Departments of Clinical Neurosciences, Psychology, and Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada; ^¶ Centre for Research in Neurodegenerative Diseases, ^|| Department of Laboratory Medicine and Pathobiology, and ^# Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; ^** Department of Pharmacology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran; Department of Pharmacology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran; and ^* Johnson & Johnson Pharmaceutical Research and Development, Spring House, PA 19477

The proteinase-activated receptors (PARs) are a novel family of G protein-coupled receptors, and their effects in neurodegenerative diseases remain uncertain. Alzheimer’s disease (AD) is a neurodegenerative disorder defined by misfolded protein accumulation with concurrent neuroinflammation and neuronal death. We report suppression of proteinase-activated receptor-2 (PAR2) expression in neurons of brains from AD patients, whereas PAR2 expression was increased in proximate glial cells, together with up-regulation of proinflammatory cytokines and chemokines and reduced IL-4 expression (p < 0.05). Glial PAR2 activation increased expression of formyl peptide receptor-2 (p < 0.01), a cognate receptor for a fibrillar 42-aa form of -amyloid (A_1–42), enhanced microglia-mediated proinflammatory responses, and suppressed astrocytic IL-4 expression, resulting in neuronal death (p < 0.05). Conversely, neuronal PAR2 activation protected human neurons against the toxic effects of A_1–42 (p < 0.05), a key component of AD neuropathogenesis. Amyloid precursor protein-transgenic mice, displayed glial fibrillary acidic protein and IL-4 induction (p < 0.05) in the absence of proinflammatory gene up-regulation and neuronal injury, whereas PAR2 was up-regulated at this early stage of disease progression. PAR2-deficient mice, after hippocampal A_1–42 implantation, exhibited enhanced IL-4 induction and less neuroinflammation (p < 0.05), together with improved neurobehavioral outcomes (p < 0.05). Thus, PAR2 exerted protective properties in neurons, but its activation in glia was pathogenic with secretion of neurotoxic factors and suppression of astrocytic anti-inflammatory mechanisms contributing to A_1–42-mediated neurodegeneration.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These studies were supported by the Canadian Institutes of Health Research (to C.P., N.V., M.D.H., and R.H.D.) and the Strafford Foundation for Alzheimer’s Research (to R.H.D. and C.P.). N.V. is an Alberta Heritage Foundation for Medical Research (AHFMR) Scholar and a Canadian Institute of Health Research New Investigator, and C.P. holds a Canada Research Chair (T1) in Neurological Infection and Immunity and is an AHFMR Senior Scholar.

² Address correspondence and reprint requests to Dr. C. Power, Department of Medicine (Neurology), 611 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada. E-mail address: chris.power{at}ualberta.ca

³ Abbreviations used in this paper: AD, Alzheimer’s disease; A_1–42, fibrillar 42-aa form of -amyloid peptide; APP, amyloid precursor protein; ER, endoplasmic reticulum; FPRL1, formyl peptide receptor-like-1; FPR2, formyl peptide receptor-2; GRP58, glucose-regulated protein 58; KO, knockout; WT, wild type; MDM, monocyte-derived macrophage; PAR, proteinase-activated receptor; RFN, rat fetal neuron; Tg, transgenic; UPR, unfolded protein response; NeuN, neuronal nuclear Ag; GFAP, glial fibrillary acidic protein.