et al., 2005; Ju et al., 2005; Lee et al., 2004). The use of GW4869 here suggests a role for nSMase2 and, indeed, this is consistent with the high expression of nSMase2 in brain (Hofmann et al., 2000). Importantly, the specific inhibition of nSMase2 using an antisense strategy abolished the Aβ effects, further supporting a role for nSMase2 in the Aβ response (Lee et al., 2004; Yang et al., 2004). Finally, research has also shown that the N-SMase inhibitors, GM4869, can downregulate Aβ levels, and that ceramide can stimulate Aβ biogenesis by stabilizing beta-site amyloid precursor protein-cleaving enzyme 1 (Grimm et al., 2005; Puglielli et al., 2003). This suggests that nSMases can further enhance Aβ level through a feedback mechanism. Importantly, there is evidence of altered sphingolipid metabolism in the brains of AD patients with both elevated ceramide and reduced SM levels being reported (He et al., 2008). Moreover, in the same report, Aβ induced both acid SMase and N-SMase activities in neuronal cell cultures, suggesting that both SMases might collaborate and contribute to Aβ signaling. Taken together, these data strongly suggest that N-SMase activation, likely the nSMase2 isoform, contributes at least partially to Aβ cytotoxicity and may be a
