Apolipoprotein E deficiency increased microglial activation/CCR3 expression and hippocampal damage in kainic acid exposed mice Rui-Sheng Duan a , Zhiguo Chen a , Ying-Chun Dou a , Hernan Concha Quezada b , Inger Nennesmo c , Abdu Adem d , Bengt Winblad a , Jie Zhu a,e, ⁎ a Division of Experimental Geriatrics (Novum, plan 5), Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden b Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden c Division of Pathology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden d Department of Pharmacology, Faculty of Medicine and Health Science, United Arab Emirates University, United Arab Emirates e Department of Neurology, the First Hospital, Jilin University, Changchun, China Received 5 April 2006; revised 27 June 2006; accepted 28 June 2006 Available online 17 August 2006 Abstract Apolipoprotein E (apoE) down-regulates microglial activation and the secretion of inflammatory molecules in an isoform specific fashion (E2 > E3 > E4); the E4 isoform is over-represented in Alzheimer cases while E2 is under-represented. To better define the role of apoE in neurodegeneration, we contrasted apoE knockout (n = 38) and wild-type mice (n =41) with respect to seizure activity, mortality, locomotion, hippocampal microglial activation/chemokine receptor expression, and damage to the hippocampus after nasal administration of kainic acid (KA) (water as controls). Mice lacking apoE demonstrated more hunching and less rearing, more damage to neurons in the CA3 region (mean histopathologic score: 3.7 vs. 1.6, p < 0.05), greater microglial activation confirmed by high levels of CD11b and CD86 expression in hippocampus (CD11b p < 0.01, CD86 p < 0.05), and a greater percentage of activated microglia expressing CC chemokine receptors 3 (CCR3) (p <0.05). Taken together, these findings imply that apoE modulates hippocampal damage induced by KA and found early in the sequence of human Alzheimer's brain changes, by modulating microglial activation. © 2006 Elsevier Inc. All rights reserved. Keywords: apoE; CCR3; Kainic acid; Microglia; Neurodegeneration Introduction Apolipoprotein E (apoE) is a 34 kDa glycosylated protein with the main functions of lipid transport and redistribution between tissues. ApoE exhibits three isoforms (E2, E3, and E4) in human due to the differences at amino acid residues 112 and 158, which are responsible for the isoform-specific effects of apoE. However, there is only one isoform of apoE in mouse and it behaves like human apoE3 (Strittmatter and Bova Hill, 2002). It is suggested that apoE deficiency in mice mimics the human apoE4 status (Buttini et al., 1999; Sheng et al., 1998). In the central nervous system (CNS), apoE is synthesized and secreted by glial cells, in particular astrocytes and is vital for neuronal maintenance, repair, and neurotrophy, as well as immunomodulation (Beffert et al., 1998; Refolo and Fillit, 2004). ApoE can down-regulate microglial activation and secretion of inflammatory molecules such as TNF-α, IL-1β, and nitric oxide (Laskowitz et al., 1997, 1998, 2001; Lynch et al., 2001). Furthermore, apoE suppressed IL-1 and TNF-α secretion in an isoform specific fashion (E2 > E3 > E4) (Maezawa et al., 2006). Growing evidence suggests that apoE4 isoform is a main genetic risk factor for a large range of neurodegenerative diseases, including Alzheimer's disease (AD), multiple sclerosis (MS), Down syndrome, and Wilson's disease (Chapman et al., 2001; Rubinsztein et al., 1999), and is also associated with poor outcome after stroke and brain injure. Protective effects of apoE3 and pathogenic effects of apoE4 have been found in clinical and Experimental Neurology 202 (2006) 373 – 380 www.elsevier.com/locate/yexnr ⁎ Corresponding author. Division of Experimental Geriatrics (Novum, plan 5), Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden. Fax: +46 8 58585470. E-mail address: Jie.Zhu@ki.se (J. Zhu). 0014-4886/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2006.06.013