Over time, the compensatory mechanisms fail, cellular damage

accumulates, and FTD pathology and symptoms evolve. The compensatory mechanisms that keep the disease “in check” for half a century are poorly understood, and it is not known if this compensation is mediated through a Wnt-dependent signaling pathway. However, it is very likely that this part of the protective-adaptational response will involve additional, non-Wnt-dependent processes ( Kumar-Singh, 2011), potentially including growth factor-related signaling cascades for endogenous neuroprotection ( Saragovi et al., 2009). Current FTD drug find more discovery approaches are targeting pathways of TDP-43 and tau, with a rationale that the new drugs should either prevent formation or increase clearance of these protein aggregates ( Trojanowski et al., 2008). So, could modulation

of the Wnt signaling pathway achieve this goal? Regardless of the enticing findings of the current study, there is no clear-cut answer to this question, and one can only be cautiously optimistic. Wnt/β-catenin signaling is widespread in the whole body (from www.selleckchem.com/products/VX-809.html brain to bone and muscle), and it is conceivable that systemic modulation of the Wnt pathway might result in numerous and potentially serious side effects ( Takahashi-Yanaga and Sasaguri, 2007). Dipeptidyl peptidase In addition, the in vitro cell line and in vivo mouse models might not fully recapitulate the critical features of the human disease. Finally, the most beneficial effect of Wnt pathway modulation would be expected during the latent phase of the disease: any beneficial effect of Wnt modulation could be diminished by the time that the diagnosis is made and/or the inflammatory and degenerative changes arise. Given that disease pathophysiology encompasses both neuronal and glial changes, what is

the relationship between these two deficits? Previous studies indicated that GRN-deficient macrophages and microglia were cytotoxic to hippocampal cells in vitro, and that GRN-deficient hippocampal slices were hypersusceptible to deprivation of oxygen and glucose (Yin et al., 2010). Thus, while the present results by Rosen et al. (2011) argue for a strong neuronal pathology in response to reduced GRN levels, early contribution of glial dysfunction to the FTD pathology cannot be excluded. Both glia and neurons express GRN from early development (Ahmed et al., 2007), and microglia lacking GRN may become activated, triggering neuronal-glial interactions that can further accelerate neuronal degeneration and cell death.