Neurobiology of Aging 31 (2010) 614–624 Memory loss caused by -amyloid protein is rescued by a  3 -adrenoceptor agonist Marie E. Gibbs a,* , Danuta Maksel b , Zoe Gibbs c , Xu Hou b , Roger J. Summers d , David H. Small b,e a Department of Anatomy and Developmental Biology, Monash University, Clayton Campus, Wellington Road, Clayton, Victoria 3800, Australia b Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia c Department of Psychology, Monash University, Clayton, Victoria 3800, Australia d Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia e Menzies Research Institute, Hobart, Tasmania 7000, Australia Received 30 December 2007; received in revised form 20 April 2008; accepted 21 May 2008 Available online 15 July 2008 Abstract Accumulation of the neurotoxic -amyloid protein (A) in the brain is a key step in the pathogenesis of Alzheimer’s disease (AD). Although transgenic mouse models of AD have been developed, there is a clear need for a validated animal model of A-induced amnesia which can be used for toxicity testing and drug development. Intracranial injections of A 1–42 impaired memory in a single trial discriminative avoidance learning task in chicks. Memory inhibition was closely associated with the state of aggregation of the A peptide, and a scrambled-sequence of A 1–42 peptide failed to impair memory. A had little effect on labile (short-term and intermediate) memory, but blocked consolidation of memory into long-term storage mimicking the type of anterograde amnesia that occurs in early AD. Since noradrenaline exerts a modulatory influence on labile memory in the chick, we examined the effects of two -adrenoceptor (AR) agonists on A-induced amnesia. A  3 -AR agonist (CL316243), but not a  2 -AR agonist, rescued A-induced memory loss, suggesting the need for further studies on the role of  3 -ARs in AD. © 2008 Elsevier Inc. All rights reserved. Keywords: Chick; Amyloid; Abeta; Dementia; Memory; Alzheimer’s disease; Neurotoxicity; Passive avoidance 1. Introduction Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. Typically the disease is characterized in its earliest stages by memory problems. Initially patients may have trouble remembering recent events, but as the dis- ease spreads, older and more established memories are lost. Wandering and disorientation occur and as the disease pro- gresses, the symptoms worsen (Storey et al., 2001). It is now recognized that AD is caused by a build-up of neurotoxic A in the brain (Small et al., 2001; Walsh and Selkoe, 2004). A peptides, particularly the longer species such as A 1–42 , are considered to be the major culprits in * Corresponding author. Tel.: +61 3 9905 2714; fax: +61 3 9905 8192. E-mail address: marie.gibbs@med.monash.edu.au (M.E. Gibbs). disease pathogenesis. A 1–42 aggregates more readily than the more commonly produced A 1–40 (Jarrett and Lansbury, 1993). A 1–42 can aggregate to form oligomers, protofib- rils that ultimately lead to the formation of amyloid plaques. However, recent studies suggest that it is the oligomeric or low molecular weight protofibrillar A species, rather than the amyloid plaques, that are the most neurotoxic (Klein et al., 2001; Walsh and Selkoe, 2004). While much of the focus in the field of AD has been on the chronic lesions that characterize the disease (amy- loid plaques, neurofibrillary tangles, gliosis, cell death), it is increasingly recognized that A may exert effects that are acute and independent of long-term chronic neurode- generation (Palop et al., 2006). For example, oligomeric A can rapidly alter calcium homeostasis and disrupt long-term potentiation (LTP) (Klein et al., 2001; Walsh and Selkoe, 0197-4580/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2008.05.018