In line with this, we observed a protective

effect on amyloid plaque formation and memory function by deleting the NOS2 gene from APP/PS1 mice. Our data are in accordance with a previous report using the Tg2576 mouse model crossbred with the human PS1 A246E mutation (Nathan et al., 2005). In addition, we observed similar effects after oral long-term application of the NOS2-specific substrate analog inhibitor L-NIL. Besides its selectivity (23-fold over NOS1 and 49-fold over NOS3) KU-55933 cell line (Moore et al., 1994 and Alderton et al., 2001), the oral bioavailability and its brain penetration have been demonstrated (Rebello et al., 2002). Of note, the safety of L-NIL has already

been demonstrated in patients suffering from asthma and in healthy controls (Hansel et al., 2003). Importantly, improved spatial learning and memory in NOS2 (−/−) or L-NIL-treated APP/PS1 mice may well be causally linked to the nitration of Aβ1-42 as the latter decreased hippocampal long-term potentiation more effectively when compared to nonnitrated Aβ1-42, suggesting that nitration of Aβ may exert a direct effect on synaptic transmission even before its deposition in plaques. This is additionally supported by the observation that deletion of NOS2 or L-NIL treatment in young APP/PS1 mice results in improved LTP. Nevertheless, additional Adenylyl cyclase NO-mediated effects, likely to be independent of nitrated Aβ, that protect from Aβ-induced suppression Stem Cell Compound Library of LTP have been reported (Wang et al., 2004). Further, the reduction of Aβ in APP/PS1 NOS2 (−/−) mice may lower the production of proinflammatory cytokines

by activated microglia and astrocytes and thereby protect from LTP suppression (Hauss-Wegrzyniak et al., 2002, Griffin et al., 2006, Tancredi et al., 1992 and Tancredi et al., 2000). In contrast, a beneficial role of NOS2 in an AD mouse model expressing the APP Swedish mutation has been suggested. Deletion of NOS2 resulted in increased Aβ deposition and improved spatial memory (Wilcock et al., 2008, Colton et al., 2006 and Colton et al., 2008). Even so there has been no mechanistic explanation for the changes in Aβ burden in this study, a main difference to our study is the usage of an AD mouse model lacking a PS1 transgene, which may account for the opposite effects observed in this study and in a previous one (Nathan et al., 2005). Colton et al. argued that the enhanced upregulation of NOS2 is an overexpression artifact of the PS1 transgene caused by an inflammatory response within resident immune cells, as evidenced in vitro by Lee et al. (2002). However, such an effect has not been observed in rodent AD models or in patients with sporadic AD.