Based on the evidence presented above demonstrating that molecular players of FAD, i.e. APP and metabolites, PS1, γ-, α- and potentially β-secretase play a role in neurogenesis, it is reasonable to assume that mutations in these players and/or their dysfunction would compromise neurogenesis in both cell-autonomous and non-cell-autonomous manner. Indeed, recent studies demonstrate that microglia-secreted soluble factors may play a role in regulation of hippocampal neurogenesis, and that microglia derived from the brains of FAD-linked mutant PS1 variants secret altered levels of soluble signaling factors, suggesting a non-cell-autonomous effect of FAD on hippocampal neurogenesis (Choi et al., 2008). This discussion underscores the need to perform studies in which select metabolites are exclusively expressed within, or exclusively secreted from specific cell populations.
