Neurobiology of Aging 28 (2007) 1009–1014 The increased activity of BACE1 correlates with oxidative stress in Alzheimer’s disease Roberta Borghi a,∗ , Stefania Patriarca b , Nicola Traverso b , Alessandra Piccini a , Daniela Storace c , Anna Garuti c , Gabriella Cirmena c , Patrizio Odetti c , Massimo Tabaton a a Department of Neuroscience, Ophthalmology and Genetics, University of Genova, Via De Toni 5, 16132 Genova, Italy b Department of Experimental Medicine, University of Genova, Via Alberti 2, 16132 Genova, Italy c Department of Internal Medicine and Medical Specialties, University of Genova, Viale Benedetto XV 6, 16132 Genova, Italy Received 9 February 2006; received in revised form 20 March 2006; accepted 3 May 2006 Available online 12 June 2006 Abstract We evaluated expression, protein levels and activity of the -site cleaving enzyme (BACE1) as well as the amount of products of lipid peroxidation in frontal cortex of three groups of cases: sporadic Alzheimer’s disease (AD); control subjects (CTR); cognitively normal subjects with abundant amyloid plaques (NA). We found a significant increase of BACE1 activity and products of lipid peroxidation in brain tissue of AD cases, with normal gene expression, and non-significant elevation of protein levels. CTR and NA samples showed similar levels of BACE1 activity and oxidative products. BACE1 activity and the amount of oxidative products were significantly correlated in all cases. Moreover, both BACE1 activity and the level of 4-hydroxynonenal were correlated with the amount of -amyloid pyroglutamated 3-42, the more toxic -amyloid peptide that is characteristic of AD. These findings suggest that BACE1 activity reflects the type of A species, rather than the -amyloid plaques load. Hence, the increase of BACE1 activity occurring in sporadic AD is likely the effect, rather the cause, of A accumulation and oxidative stress. © 2006 Elsevier Inc. All rights reserved. Keywords: Alzheimer’s disease; -Amyloid; BACE1; Oxidative stress 1. Introduction Alzheimer’s disease (AD) is characterized by cerebral deposition of amyloid plaques, neurofibrillary pathology, and synaptic loss [13]. Beta-amyloid (A), the amyloid compo- nent, is a mixture of heterogeneous peptides [11] derived from two sequential endoproteolytic cleavages of the -amyloid precursor protein (APP) catalyzed by two distinct enzymes, referred to as  and -secretase [14,15]. The -site cleaving enzyme (BACE1) is highly expressed in brain tissue and colo- calizes with the intracellular sites of A production [16,19]. Various research groups have demonstrated an increase of ∗ Corresponding author. Tel.: +39 010 3538881; fax: +39 010 506938. E-mail address: robertaborghi@yahoo.it (R. Borghi). BACE1 activity in the cerebral cortex of sporadic AD, as a potential cause of A accumulation [2,4,21]. However, the reasons for the increased activity of BACE1 are unknown. Oxidative stress is a pathogenic event in AD, since the levels of oxidation products, such as 4-hydroxynonenal (HNE) and malondialdehyde (MDA), are increased in AD brain tissue in proportion to the extent of the pathologic lesions [5,12]. Oxidative stress promotes the cellular production of A, increasing either the expression of APP or the extent of - secretase cleavage [6,7,9]. We and other research groups have demonstrated that oxidants up-regulate in vitro the expres- sion and activity of BACE1 [3,17]. To study the relationship between oxidative stress, BACE1 activity, and neurodegen- eration, we investigated the expression, protein levels and activity of BACE1, the amount of HNE and MDA in brain tis- 0197-4580/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2006.05.004