Tauroursodeoxycholic acid (TUDCA) supplementation prevents cognitive impairment and amyloid deposition in APP/PS1 mice Adrian C. Lo a , Zsuzsanna Callaerts-Vegh a , Ana F. Nunes b , Cecília M.P. Rodrigues b, c, ⁎, Rudi D'Hooge a, ⁎⁎ a Laboratory of Biological Psychology, Faculty of Psychology and Educational Sciences, University of Leuven, Leuven, Belgium b Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal c Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal abstract article info Article history: Received 4 March 2012 Revised 31 August 2012 Accepted 2 September 2012 Available online 10 September 2012 Keywords: Alzheimer's disease APP/PS1 TUDCA Learning and memory Morris water maze Alzheimer's disease (AD) is a neurodegenerative disease hallmarked by extracellular Aβ 1–42 containing plaques, and intracellular neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein. Progressively, memory deficits and cognitive disabilities start to occur as these hallmarks affect hippocampus and frontal cortex, regions highly involved in memory. Connective tissue growth factor (CTGF) expression, which is high in the vicinity of Aβ plaques and NFTs, was found to influence γ-secretase activity, the molecular crux in Aβ 1–42 production. Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid that downregulates CTGF expression in hepatocytes and has been shown to possess therapeutic efficacy in neurodegenerative models. To investigate the possible in vivo therapeutic effects of TUDCA, we provided 0.4% TUDCA-supplemented food to APP/PS1 mice, a well-established AD mouse model. Six months of TUDCA supplementation prevented the spatial, recognition and contextual memory defects observed in APP/PS1 mice at 8 months of age. Furthermore, TUDCA-supplemented APP/PS1 mice displayed reduced hippocampal and prefrontal amyloid deposition. These effects of TUDCA supplementation suggest a novel mechanistic route for Alzheimer therapeutics. © 2012 Elsevier Inc. All rights reserved. Introduction Brain deposition of amyloid-beta (Aβ) is a central pathobiochemical event in Alzheimer's disease (AD). The Aβ cascade hypothesis explains how cleavage of amyloid precursor protein (APP) by the infamous γ-secretase complex (Li et al., 2009) produces toxic soluble Aβ mono- mers and oligomers that aggregate into amyloid deposits, and could gradually lead to widespread neural and glial dysfunction, memory de- fects, and ultimate dementia (Hardy and Selkoe, 2002; Selkoe, 2008; Walsh and Selkoe, 2004). Braak and Braak (1991) historically showed that amyloid deposits first occur in basal portions of the frontal, tempo- ral and occipital isocortex of the AD brain. Distinct phases of Aβ deposi- tion have been identified starting in isocortex, soon spreading to hippocampus and other allocortical regions, and eventually involving vast areas of the brain (Thal et al., 2002). By and large, Aβ neuropathol- ogy first seems to hit brain regions that are important for cognition (including learning and memory), and affect regions that play a role in other brain functions in later stages of the disease (Bero et al., 2011; Jucker and Walker, 2011; Pievani et al., 2011). Ursodeoxycholic acid (UDCA) and its taurine conjugate (TUDCA) are endogenous bile acids that are able to cross the blood–brain barrier and exert their effects on the central nervous system (Keene et al., 2001; Parry et al., 2010). Parry and colleagues reported dose-dependent in- creases in UDCA serum and cerebrospinal fluid concentrations in amyotrophic lateral sclerosis (ALS) patients after UDCA administra- tion (Parry et al., 2010). Also TUDCA enters the brain after systemic ad- ministration as TUDCA brain levels increased up to 6-fold in TUDCA- treated rats (Keene et al., 2001). Furthermore, TUDCA displayed neuroprotective activity in cellular AD models (Ramalho et al., 2008) as well as in vivo models of Huntington's and other neurodegenerative diseases (Keene et al., 2001, 2002; Rodrigues et al., 2003). Notably, TUDCA co-incubation inhibited Aβ 1-42 - and Aβ 25-35 -evoked apoptosis in PC12 neuronal cells (Ramalho et al., 2004; Viana et al., 2010). The com- pound did not affect Aβ aggregation as such (Viana et al., 2009), but was suggested to downregulate expression of connective tissue growth factor (CTGF) in hepatocytes (Castro et al., 2005), which suggests an ap- proach to influence Aβ production more indirectly (Zhao et al., 2005). Indeed, high hippocampal and neocortical expression of CTGF in post-mortem AD brains (Ueberham et al., 2003), and its co-localization with plaques and tangles suggest CTGF involvement in initiation and/or maintenance of AD neuropathology (Ueberham et al., 2003). Increased CTGF expression was accompanied by increased plaque formation (Ho et al., 2004; Zhao et al., 2005), and CTGF was shown to bind to the low-density lipoprotein-related protein receptor (LRP), which affects downstream amyloid deposition and tangle formation. Earlier work Neurobiology of Disease 50 (2013) 21–29 ⁎ Correspondence to: C. Rodrigues, iMed.UL, Faculty of Pharmacy, University of Lisbon, Lisbon 1649‐003, Portugal. ⁎⁎ Correspondence to: R. D'Hooge, Laboratory of Biological Psychology, Tiensestraat 102, B-3000 Leuven, Belgium. E-mail addresses: cmprodrigues@ff.ul.pt (C.M.P. Rodrigues), rudi.dhooge@ppw.kuleuven.be (R. D'Hooge). Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.nbd.2012.09.003 Contents lists available at SciVerse ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi