A NOVEL RAT MODEL OF ALZHEIMER’S DISEASE BASED ON LENTIVIRAL-MEDIATED EXPRESSION OF MUTANT APP S. PARSI, a  S. PANDAMOOZ, a  S. HEIDARI, a M. NAJI, b G. MORFINI, c A. AHMADIANI a,d AND L. DARGAHI e * a Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran b Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran c Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA d Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia e NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Abstract—Background: Alzheimer’s disease (AD) is charac- terized by progressive and irreversible cognitive and mem- ory impairment. The discovery of familial forms of AD (fAD) in association with specific gene mutations facilitated the generation of numerous rodent models. These models in turn proved valuable for the study of molecular mechanisms underlying AD pathogenesis, and facilitated translational research and preclinical drug development. This study aimed to introduce a new rat model of AD simulating some aspects of the sporadic cases of disease. Methods: Lentiviruses (LV) encoding human amyloid protein precursor (APP) bearing the fAD-linked Swedish and Indiana mutations (APP Sw/Ind ) were injected bilaterally in the hippocampus of adult rats. Passive avoidance and spatial memory performance were assessed 30 and 45 days post-injection, respectively. APP overexpression, intracellu- lar accumulation of b-amyloid (Ab) peptide, and astrogliosis were also evaluated using immunohistochemical proce- dures. Results: Passive avoidance memory deficit was followed by impairments in spatial memory retrieval in LV (APP Sw/Ind )- injected rats, compared to control animals. In addition, LV expression of APP Sw/Ind was associated with intraneuronal accumulation of Ab, and reactive astrocytosis, two major AD hallmarks. Conclusion: Results from this work suggest that LV-mediated delivery of APP Sw/Ind in adult rats represents a cost and time-effective animal model for the study of mechanisms underlying APP-linked fAD pathogenesis. The relevance of this animal model to the study of sporadic AD is discussed. Ó 2014 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: Alzheimer’s disease, animal model, lentiviral vector. INTRODUCTION Alzheimer’s disease (AD), currently affecting over 36 million individuals worldwide, is a neurodegenerative disorder characterized by progressive degeneration of specific neuronal populations and the concomitant loss of memory and cognitive functions (Huang and Mucke, 2012). Genetic forms of familial AD (fAD), which are inherited in an autosomal dominant manner, have been recently identified. However, little is known about genetic and environmental factors underlying sporadic AD (sAD) cases, which represent the large majority of total AD cases (Gatz et al., 2006). During the past two decades, the study of fAD animal models has increased our knowledge of pathogenic events in sAD at the molecular level, with the rationale that at least some of these events are common to both fAD and sAD forms (Laferla and Green, 2012). Neuropa- thologically, AD is defined by the accumulation of both b- amyloid (Ab) peptide in the form of extracellular plaques and hyperphosphorylated tau (s) protein in the form of intracellular neurofibrillary tangles in affected neurons (Bertram et al., 2010). Cumulative evidence indicates that neuronal dysfunction begins decades prior to its clinical presentation. Accordingly, pathological studies in fAD ani- mal models collectively indicate that neurons affected in AD degenerate following a dying-back pattern, which is characterized by early loss of synaptic function and neu- ritic connectivity (Kanaan et al., 2013). Astrocytosis and other glial and inflammation-related alterations are also observed in AD, particularly at late disease stages (Selkoe, 2002). Transgenic fAD mouse models have revealed several aspects of mechanisms involved in AD, and have also played an important role in the evaluation of therapeutic drugs aimed to prevent neuronal degeneration (Hsiao et al., 1995; Games et al., 1995). However, the failure of multiple potential therapeutic agents in clinical trials http://dx.doi.org/10.1016/j.neuroscience.2014.09.045 0306-4522/Ó 2014 IBRO. Published by Elsevier Ltd. All rights reserved. * Corresponding author. Address: NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Evin, Postal code: 19615-1178, Tehran, Iran. Tel: +98-21-22-42-97-68; fax: +98-21- 22-43-16-24. E-mail address: l.dargahi@sbmu.ac.ir (L. Dargahi).   S. Parsi and S. Pandamooz contributed equally to this work. Abbreviations: Ab, b-amyloid; AD, Alzheimer’s disease; APP, amyloid protein precursor; eGFP, enhanced green fluorescent protein; fAD, familial forms of AD; GFAP, glial fibrillary acidic protein; GFP, green fluorescent protein; LV, lentivirus; PBS, phosphate buffered saline; PFA, paraformaldehyde; RT, room temperature; sAD, sporadic AD. Neuroscience 284 (2015) 99–106 99