Insulin growth factor binding protein 7 is a novel target to treat dementia Hope Y. Agbemenyah a , Roberto C. Agis-Balboa a,1 , Susanne Burkhardt b , Ivana Delalle c , Andre Fischer a,b, ⁎ a Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Grisebachstr. 5, 37077 Göttingen, Germany b German Center for Neurodegenerative Diseases (DZNE) Göttingen, Grisebachstr. 5, 37077 Göttingen, Germany c Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA abstract article info Article history: Received 30 April 2013 Revised 13 August 2013 Accepted 17 September 2013 Available online 25 September 2013 Keywords: Insulin-like growth factor binding proteins Alzheimer Epigenetics Learning and memory Alzheimer's disease (AD) is the most common form of dementia in the elderly but effective therapeutic strategies to treat AD are not yet available. This is also due to the fact that the pathological mechanisms that drive the pathogenesis of sporadic AD are still not sufficiently understood and may differ on the individual level. Several risk factors such as altered insulin-like peptide (ILP) signaling have been linked to AD and modulating the ILP system has been discussed as a potential therapeutic avenue. Here we show that insulin-like growth factor binding protein 7 (IGFBP7), a protein that attenuates the function of ILPs, is up-regulated in the brains of AD patients and in a mouse model for AD via a process that involves altered DNA-methylation and coincides with decreased ILP signaling. Mimicking the AD-situation in wild type mice, by increasing hippocampal IGFBP7 levels leads to impaired memory consolidation. Consistently, inhibiting IGFBP7 function in mice that develop AD-like memory impairment reinstates associative learning behavior. These data suggest that IGFBP7 is a critical regulator of memory consolidation and might be used as a biomarker for AD. Targeting IGFBP7 could be a novel therapeutic avenue for the treatment of AD patients. © 2013 Elsevier Inc. All rights reserved. Introduction Alzheimer's disease (AD) is the most common neurodegenerative disorder. It currently affects more than 30 million people worldwide. This number is expected to double until 2025 due to increased life expectancies. AD arises on the pathological background of amyloid-ß-plaques, neurofibrillary tangles and severe neurodegen- eration leading to dementia (Haass and Selkoe, 2007). Expect for the few cases that develop an early onset form of AD that is caused by mutations in the amyloid precursor protein (APP) itself or the proteins that process APP (Haass and Selkoe, 2007), aging is the major risk factor for the sporadic form of AD that accounts for 98% of all cases. At present there is no effective treatment for AD and all phase III clinical trials targeting Aβ pathology have failed indicating that treatments targeted towards Aβ pathology are too late to help patients that already suffer from memory disturbances (Miller, 2012; Mullard, 2012). At the same time, such data shows that we still understand very little of the pathological mechanisms that mediate memory decline in sporadic AD. There is now emerging evidence that sporadic AD is driven by various combinations of genetic and environmental risk factors that likely differ on the individual level. One interesting observation has been a link be- tween de-regulated signaling of ILPs – that include insulin and insu- lin-like growth factors (IGF) 1 and IGF2 – and sporadic AD (Piriz et al., 2011). Several population-based studies have reproducibly shown that the risk to develop cognitive decline in elderly people is in- creased in individuals suffering from type 2 diabetes (Arvanitakis et al., 2004; Luchsinger, 2012). Such findings inspired subsequent studies and one promising line of research has been the analysis of ILP signaling cascades for their role in AD pathogenesis (Piriz et al., 2011). The role of IGF1 and IGF2 – that are both expressed in the adult brain (Agis-Balboa et al., 2011) – in AD pathogenesis has been studied (Carro et al., 2002). In particular IGF1 has been linked to neuroprotection (Dudek et al., 1997; Russo et al., 2005) and administration of IGF1 or insulin was found to have beneficial effects in humans suffering from ataxia or AD (Arpa et al., 2011; Craft et al., 2011). Such data are in line with findings demon- strating a role of ILPs in memory formation, neuronal and synaptic plasticity as well as adult neurogenesis (Agis-Balboa et al., 2011; Castro-Alamancos and Torres-Aleman, 1994; Chen et al., 2011; Llorens- Martín et al., 2009). Despite such promising results there is also evidence that age-related neurodegenerative processes such as amyloid deposi- tion are promoted by IGFs and IGF1 in particular (Araki et al., 2009; Cohen and Dillin, 2008; Cohen et al., 2009; Freude et al., 2009). As a so- lution to this paradox it has been suggested that each organ has probably an optimal level of ILP signaling and that both decreased and increased ILP levels could contribute to neurodegenerative diseases depending on the specific context (Cohen and Dillin, 2008). Thus, rather than targeting for example IGF1 it would be desirable to learn more on the mechanisms that mediate fine-tuning of the ILP system in the adult brain. A line of Neurobiology of Disease 62 (2014) 135–143 ⁎ Corresponding author at: Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, University Goettingen, German Center for Neurodegenerative Diseases (DZNE) Goettingen, Grisebachstr. 5, D-37077 Goettingen, Germany. E-mail address: afische2@gwdg.de (A. Fischer). Available online on ScienceDirect (www.sciencedirect.com). 1 Present address: Institute of Biomedical Research of Vigo, University Hospital of Vigo (CHUVI — Hospital Rebullón), Puxeiros s/n, 36415 Mos (Pontevedra), Spain. 0969-9961/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.nbd.2013.09.011 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi