Figure 3. Mitochondria-associated membrane and AD.

MAM is a specialized, lipid raft–like subdomain of the ER that communicates with mitochondria. APP is processed first by β-secretase in endosomes to produce C99. C99 then translocates to the ER (by an unknown mechanism), where it is cleaved rapidly by MAM-localized γ-secretase. In AD, however, this process is impaired, leading to the abnormal accumulation of C99 in the MAM, which correlates with increased conversion of sphingomyelin to ceramide via an upregulation of sphingomyelinase activity. In turn, the elevated ceramide compromises ETC assembly and ATP production.