Sustained astrocytic clusterin expression improves remodeling after brain ischemia Anouk Imhof, a,b,e Yves Charnay, a Philippe G. Vallet, a Bruce Aronow, c Eniko Kovari, a Lars E. French, d Constantin Bouras, a and Panteleimon Giannakopoulos a,b, * a Department of Psychiatry, HUG, Belle-Ide ´e, 2, ch. du Petit-Bel-Air, 1225 Che ˆne-Bourg Geneva, Switzerland b Division of Old Age Psychiatry, University of Lausanne School of Medicine, CH-1008 Prilly, Switzerland c Division of Molecular Developmental Biology Children’s Hospital Research Foundation, Cincinnati, OH 45229-3039, USA d Division of Dermatology, University Hospitals of Geneva, CH-1211 Geneva, Switzerland e Center of Psychiatric Neurosciences, University of Lausanne School of Medicine, 1008 Prilly, Switzerland Received 23 July 2005; revised 15 November 2005; accepted 17 November 2005 Available online 10 February 2006 Clusterin is a glycoprotein highly expressed in response to tissue injury. Using clusterin-deficient (CluÀ/À) mice, we investigated the role of clusterin after permanent middle cerebral artery occlusion (MCAO). In wild-type (WT) mice, clusterin mRNA displayed a sustained increase in the peri-infarct area from 14 to 30 days post-MCAO. Clusterin transcript was still present up to 90 days post-ischemia in astrocytes surrounding the core infarct. Western blot analysis also revealed an increase of clusterin in the ischemic hemisphere of WT mice, which culminates up to 30 days post-MCAO. Concomitantly, a worse structural restoration and higher number of GFAP-reactive astrocytes in the vicinity of the infarct scar were observed in CluÀ/À as compared to WT mice. These findings go beyond previous data supporting a neuroprotective role of clusterin in early ischemic events in that they demonstrate that this glycoprotein plays a central role in the remodeling of ischemic damage. D 2005 Elsevier Inc. All rights reserved. Keywords: Astrocytes; Apolipoprotein J; Clusterin-deficient mice; Middle cerebral artery occlusion; Neuroprotective effect Ischemic cerebral stroke is the third cause of death and a major cause of handicap in western countries (Dirnagl et al., 1999). In order to improve therapeutic management and reduce health care’s burden, it is crucial to explore the complex molecular phenomena which take place in the course of this disorder. Soon after ischemic brain stroke, cell death and tissue devastation caused by free radicals, excitotoxicity and inflammation involve a number of signaling pathways each one representing potential targets for early therapeutic intervention (Dirnagl et al., 1999; Slevin et al., 2005). Brain tissue directly affected by a stroke can be divided into a necrotic core region and a surrounding peri-infarct area (also referred to as ischemic penumbra) which initially has flow rates adequate for survival but subsequently may become recruited in the infarction process (Barinaga, 1998; Weinstein et al., 2004). The long-term survival of neurons in the peri-infarct area in which the destiny of nerve cells is not fated mainly depends on the environment’s ability to restore local brain homeostasis (Neder- gaard and Dirnagl, 2005). From this point of view, better knowledge of late molecular and cellular adaptive responses to ischemia may offer new therapeutic perspectives. Although an impressive number of recent studies attempted to elucidate the biological background of the early post-ischemic period (see Dirnagl et al., 1999; Slevin et al., 2005), the molecular determinants of the long-term structural restoration in cerebral ischemia are surprisingly still unknown. Among glial cell populations activated in the peri-infarct area after stroke (Nedergaard and Dirnagl, 2005; Panickar and Noren- berg, 2005), astrocytes have been traditionally associated with certain essential functions such as maintaining a favorable chemical environment and fueling of neurons (Dienel and Hertz, 2005; Pellerin and Magistretti, 2004). Various types of brain injuries induce reactive astrogliosis characterized by cellular morphological changes and a marked upregulation of many genes including those encoding glial fibrillary astrocyte protein (GFAP), protein S100 beta (Yasuda et al., 2004), trophic factors (Swanson et al., 2004; Trendelenburg and Dirnagl, 2005), and clusterin (Cheng et al., 1994; Jones and Jomary, 2002; Pasinetti et al., 1994; Rosenberg and Silkensen, 1995; Walton et al., 1996; Wiggins et al., 2003; Wilson and Easterbrook-Smith, 2000; Zoli et al., 1993). This latter multifunctional heterodimeric glycoprotein (also called apolipoprotein J) is constitutively synthesized by a variety of tissues and found in most biological fluids (Jenne and Tschopp, 0969-9961/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2005.11.009 * Corresponding author. Department of Psychiatry, HUG, Belle-Ide ´e, 2, ch. du Petit-Bel-Air, 1225 Che ˆne-Bourg Geneva, Switzerland. E-mail address: Panteleimon.Giannakopoulos@medecine.unige.ch (P. Giannakopoulos). Available online on ScienceDirect (www.sciencedirect.com). www.elsevier.com/locate/ynbdi Neurobiology of Disease 22 (2006) 274 – 283