The following are the supplementary data

The following are the supplementary data related to this article.
Acknowledgment This work was supported by the DIR, NIDCR and NIAID of the IRP, NIH, DHHS. We thank the patients, healthy volunteers and clinical research staff for their contributions.
Introduction The neurogenerative process in patients with Alzheimer\'s disease (AD) is characterized by synaptic loss (Overk and Masliah, 2014) and loss of cholinergic, glutaminergic and GABA-ergic neurons (DeKosky et al., 1996; Masliah, 1995, 2001; Masliah et al., 2006; Scheff et al., 1990; Terry et al., 1991; Trojanowski et al., 1995). In addition, more recent studies suggest that alterations in adult neurogenesis in the hippocampus might also contribute to the neurodegenerative process in AD (Dong et al., 2004). There is some controversy over whether neurogenesis is increased (Jin et al., 2004) or decreased (Boekhoorn et al., 2006; Li et al., 2008) in AD. Recent studies suggest that apparent increases in neurogenesis in AD patients may be related to glial and vasculature-associated changes (Boekhoorn et al., 2006). Studies in a number of animal models of Familial AD have shown that neurogenesis is reduced (Dong et al., 2004; Donovan et al., 2006; Haughey et al., 2002; Rockenstein et al., 2007). The mechanisms of neurodegeneration in AD are not completely clear, however progressive accumulation of amyloid beta (Aβ) with the formation of oligomers appears to trigger a complex cascade of events that includes activation of several kinases including glycogen synthetase kinase (GSK3β) and cyclin dependent kinase-5 (CDK5) (Crews and Masliah, 2010; Engmann and Giese, 2009; Shukla et al., 2012) leading to aberrant post-transcriptional modification of the microtubule binding protein—Tau (Gong and Iqbal, 2008). Moreover, other studies suggest that deficient transport or expression of neurotrophic factors (NTF) (e.g., nerve growth factor [NGF], SGC707 derived neurotrophic factor [BDNF]) and their receptors might be involved (Peng et al., 2005; Schindowski et al., 2008; Scott et al., 1995). For this reason, experimental therapies for AD involve reducing the Aβ load, blocking kinases such as GSK3β and CDK5, reducing Tau and replacement therapies with NTFs (Blurton-Jones et al., 2009; Nagahara et al., 2009; Tuszynski, 2007; Tuszynski et al., 2005). However, given the advanced clinical stage at which several patients with AD present, alternative therapies are under consideration including replacement therapy with neuronal stem cell grafts. For example, previous studies have shown that neural stem cells (NSC) transferred into the hippocampus of AD transgenic (tg) models improve cognition via BDNF (Nagahara et al., 2009, 2013) and reduce Tau and reelin accumulation in aged Ts65DN model of Down\'s syndrome (Kern et al., 2011). Moreover, transplantation of NSC derived from induced pluripotent stem cells (iPSC) restore memory in amyloid precursor protein (APP) tg (Fujiwara et al., 2013) and APP/Presenilin-1 (PS1) mice (Zhang et al., 2014a) supporting the notion that treatment with NSCs might be of useful in AD patients. However, a potential problem is the reduced viability of the transplanted cells given the noxious micro-environment in the brain of patients with AD. For example, we have recently shown that under baseline conditions NSC display reduced viability when transplanted into the brains of APP mice, however when these cells are modified to express the Aβ degrading enzyme, neprilysin, the stem cells are more prone to survive (Blurton-Jones et al., 2014). Therefore, adjuvant therapies that enhance survival of grafted stem cells might be important. Among them, we have considered the potential of combining stem cells with Cerebrolysin™ (CBL) a peptide mixture with neurotrophic-like properties that improves cognition in patients with mild to moderate AD (Alvarez et al., 2006, 2011; Plosker and Gauthier, 2009, 2010; Ruther et al., 1994, 2000). CBL has been shown to be protective in experimental models of excitotoxicity (Veinbergs et al., 2000) and stroke (Onishchenko et al., 2008; Ren et al., 2007; Zhang et al., 2010). In addition, CBL is neurotrophic in APP tg models of AD by promoting synaptic formation and neurogenesis (Blanchard et al., 2010a,b; Chohan et al., 2011; Rockenstein et al., 2002, 2003, 2005, 2007). The protective effects of CBL in AD-like models involve different mechanisms including regulation of GSK3β and CDK5 signaling, control of APP metabolism and anti-apoptotic effects mediated by expression of endogenous neurotrophic factors (Ubhi et al., 2013). In this context, the main objective of this study was to investigate whether CBL is capable of enhancing the survival of transplanted NSCs. We found NSC survival progressively declined with age in APP tg mice when compared to controls and that adjuvant therapy with CBL enhanced survival of the BrdU tagged grafted NSC. This study supports the notion that CBL might be a potentially useful adjuvant therapy in combination with NSCs.