In addition to the functions outlined above, the N-SMase/ceramide pathway has also been implicated in neuronal degeneration, particularly in Alzheimer’s Disease (AD) (Jana et al., 2009). Amyloid-β peptide (Aβ) is a major constituent of senile plaques in the brains of AD patients, and a number of reports have demonstrated that Aβ plays roles in the pathogenesis of AD and is toxic to neurons and oligodendrocytes (Grimm et al., 2005; Yang et al., 2004). Indeed, several studies have implicated the nSMase/ceramide pathway in the development of AD through Aβ. This is suggested by a number of lines of evidence. First, the treatment of cultured neuronal cells with Aβ was reported to induce N-SMase activity and ceramide accumulation (Jana and Pahan, 2004). Additionally, the cytotoxic effects of Aβ were abrogated by various pharmacological inhibitors of N-SMases, including, GW4869, 3-O-Me-SM and N-acetyl-L-cysteine (Grimm 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
