, 2001 and Weihl et al., 1999); and (2) Aβ can both directly and indirectly interfere with canonical Wnt signaling and that this interference compromises neuronal survival ( Caricasole et al., 2004 and Scali et al., 2006). Wnt signaling therefore may provide a bridge between

neurodevelopment and neurodegeneration ( Geschwind and Miller, 2001 and Jackson et al., 2002). It is still an open question as to whether loss of GRN causes FTD pathology through a cell autonomous or noncell autonomous mechanism. Loss of GRN may increase neuronal vulnerability, conferring an intrinsic property in which neurodegeneration is more likely. Alternatively, microglia lacking GRN may become hyperactive, creating a poor extrinsic Lenvatinib cost environment

that leads to neuronal death. This is a complex issue because GRN is a secreted protein, the form of GRN that is clinically relevant to FTD is currently unknown, and GRN transcripts are decreased in blood, but are paradoxically increased in GRN+ diseased brain (Chen-Plotkin et al., 2010). The data that we present here, in which GRN loss is sufficient to produce cell death in the absence of microglia, shows that neuronal GRN deficiency is sufficient to significantly reduce neuronal survival, a finding important for potential therapeutics development. While these data argue that GRN loss can indeed increase neuronal vulnerability, they do not preclude the compounding selleck inhibitor involvement of microglia in the pathophysiology of FTD in patient brain, which may form a vicious cycle (Pickford et al., 2011 and Yin et al., 2010). Here we provide data from multiple systems showing that FZD2 expression increases with GRN loss. We then performed Parvulin a proof of principle experiment, indicating that this increase may be protective. Classically, signaling through the FZD2 receptor activates the noncanonical Wnt signaling pathway ( Oishi et al., 2003). This suggests

that modulation of this pathway may have therapeutic relevance; previous work has shown that noncanonical Wnt agonists can be protective in other forms of dementia ( Inestrosa and Toledo, 2008). As opposed to canonical Wnt signaling, which has already been established as a major player in neurodegeneration ( Hooper et al., 2008 and Toledo et al., 2008), these data indicate a role for Wnt signaling independent of GSK-3β and β-catenin in neurodegenerative pathology. Additionally, FZD2 is the initial change that precedes alterations in other Wnt pathway members in mouse in vivo at stages well prior to neurodegeneration or neuronal loss. Thus, FZD2 represents a primary target in that it is a consistent and early upregulated gene in the context of GRN loss.