BACE1 (-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time Yi Luo, a Brad Bolon, a Michael A. Damore, a Dan Fitzpatrick, a Hantao Liu, a Jianhua Zhang, a Qiao Yan, a Robert Vassar, b and Martin Citron a, * a Amgen Inc., Thousand Oaks, CA, USA b Northwestern University, Feinberg School of Medicine, Chicago, IL, USA Received 17 December 2002; revised 13 May 2003; accepted 11 June 2003 Abstract The formation of Alzheimer’s A peptide is initiated when the amyloid precursor protein (APP) is cleaved by the enzyme -secretase (BACE1); inhibition of this cleavage has been proposed as a means of treating Alzheimer’s disease. (AD) We have previously shown that young BACE1 knockout mice (BACE1 KO) do not generate A but in other respects appear normal. Here we have extended this analysis to include both gene expression profiling and phenotypic assessment of older BACE1 KO animals to evaluate the impact of chronic A deficiency. We did not detect global compensatory changes in neural gene expression in young BACE1 KO mice. In particular, expression of the -secretase homolog BACE2 was not upregulated. Furthermore, we found no structural alterations in any organ, including all central and peripheral neural tissues, of BACE1 KO mice up to 14 months of age. Aged BACE1 KO mice engineered to overexpress human APP (BACE1 KO/APPtg) did not develop amyloid plaques. These data provide evidence that neither -secretase nor A plays a vital role in mouse physiology and that chronic -secretase inhibition could be a useful approach in treating AD. © 2003 Elsevier Inc. All rights reserved. Keywords: Alzheimer’s disease; Amyloid; A; -Secretase; BACE; Knockout Introduction At present, the generation of amyloid -peptide (A) is widely held to play an early and critical role in the patho- genesis of Alzheimer’s disease (Hardy and Selkoe, 2002). Consequently, the mechanisms of A generation and clear- ance have attracted considerable attention, both from the standpoint of basic scientific understanding and from a therapeutic perspective. A is generated from the large precursor protein amyloid precursor protein (APP) by the sequential action of two proteases, - and -secretase. -Secretase has been identi- fied as -site APP-cleaving enzyme 1 (BACE1) which, together with its homolog BACE2, forms a novel subfamily of transmembrane aspartic proteases within the pepsin fam- ily (for review, see Vassar and Citron, 2000). We and others have recently demonstrated that young BACE1 knockout mice (BACE1 KO or -/- mice) fail to generate A but appear to be normal in other respects (Cai et al., 2001; Luo et al., 2001; Roberds et al., 2001). In the present work, we have extended our analysis of BACE1 KO mice in two important ways. First, we used gene expression profiling to explore the potential for com- pensatory changes in neural genes that could contribute to the “normal” phenotype in young mice. Our findings show that global gene expression in brain is not changed in BACE1 KO mice and in particular that the homolog BACE2 is not upregulated in the absence of BACE1. Sec- ond, we investigated the impact of chronic BACE1 block- ade by performing detailed anatomic and clinical pathology assessments on aged BACE1 KO mice. Our data indicate that neither functional nor structural alterations—including amyloid plaques or other neural lesions— develop over * Corresponding author. Department of Neuroscience, M/S 29-2-B, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320. Fax: +1-805-480-1347. E-mail address: mcitron@amgen.com (M. Citron). R Available online at www.sciencedirect.com Neurobiology of Disease 14 (2003) 81– 88 www.elsevier.com/locate/ynbdi 0969-9961/03/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0969-9961(03)00104-9