Figure 7. Model for how FAD mutations trigger pathogenesis and possible implications for sporadic Alzheimer’s disease.

In healthy neurons, the γ-Secretase complex can effectively process C99 and the enzyme’s many other membrane-bound substrates. FAD mutations in APP result in stalled γ-Secretase complexes bound to C99 substrate or Aβ intermediate. FAD mutations in presenilin result in stalled interaction between γ-Secretase and its substrates (not restricted to C99). In sporadic late-onset AD, in the absence of mutations in APP or presenilins, other factors, such as altered membrane fluidity or thickness, may stabilize E-S complexes, thereby triggering synaptic degeneration.