BACE1 (-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes Steve M. Harrison, a,1 Alex J. Harper, b,1 Julie Hawkins, b Graham Duddy, a Evelyn Grau, c Pippa L. Pugh, b Panida H. Winter, d Claire S. Shilliam, d Zoe ¨ A. Hughes, d Lee A. Dawson, d M. Isabel Gonzalez, b Neil Upton, b Menelas N. Pangalos, b and Colin Dingwall b, * a Department of Comparative Genomics, GlaxoSmithKline, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, UK b Neurology and Gastroenterology Center of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, UK c The Sanger Centre, Wellcome Trust Genome Campus, Hinxton, Cambs CB10 1SA, UK d Psychiatry Center of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, UK Received 12 December 2002; revised 12 June 2003; accepted 17 June 2003 Abstract BACE1 is a key enzyme in the generation of A, the major component of senile plaques in the brains of Alzheimer’s disease patients. We have generated transgenic mice expressing human BACE1 with the Cam Kinase II promoter driving neuronal-specific expression. The transgene contains the full-length coding sequence of human BACE1 preceding an internal ribosome entry site element followed by a LacZ reporter gene. These animals exhibit a bold, exploratory behavior and show elevated 5-hydroxytryptamine turnover. We have also generated a knockout mouse in which LacZ replaces the first exon of murine BACE1. Interestingly these animals show a contrasting behavior, being timid and less exploratory. Despite these clear differences both mouse lines are viable and fertile with no changes in morbidity. These results suggest an unexpected role for BACE1 in neurotransmission, perhaps through changes in amyloid precursor protein processing and A levels. © 2003 Elsevier Inc. All rights reserved. Introduction Alzheimer’s disease (AD) is the most prevalent of all adult-onset neurodegenerative disorders and is character- ized by a progressive memory loss that may also be asso- ciated with other neuropsychiatric behavioral impairments. The principle neuropathological features of this disease are overt neuronal and synaptic loss, extracellular accumulation of amyloid plaques, composed primarily of amyloid -pep- tide (A) deposits, and intracellular neurofibrillary tangles composed of hyperphosphorylated tau (see Hardy and Selkoe, 2002). These defining hallmarks of AD neuropa- thology have been the focus of intense research over the past two decades and have led to the identification of the secretase enzymes involved in A production, as well as to the identification of a variety of kinases that can potentially hyperphosphorylate tau in vivo. A peptide is an internal peptide cleaved from a type 1 membrane-spanning precursor protein, the amyloid precur- sor protein (APP) through two sequential proteolytic cleav- age events catalyzed by - and -secretases. Several amy- loid-depositing mouse models have been generated using different promoters, constructs, and APP mutations linked to familial forms of the disease (see Janus et al., 2000; Emilien et al., 2000b; Van Leuven, 2000). In all of these models, there is an age-dependent increase in brain A * Corresponding author. Fax: +01279-622555. E-mail address: Colin_2_Dingwall@gsk.com (C. Dingwall). 1 Contributed equally to this work. Molecular and Cellular Neuroscience 24 (2003) 646 – 655 www.elsevier.com/locate/ymcne 1044-7431/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1044-7431(03)00227-4