**7. AICD turnover**

The turnover of APP is very fast (with a half life of cell surface APP of about 30-40 minutes only [81] and only about 10% of APP are estimated to reach the cellular membrane, whereas the majority of APP locates to the Golgi apparatus and trans-Golgi network [10]. APP not shed at the surface is internalized within minutes [82], delivered to endosomes, and if not degraded in lysosomes recycled to the cell surface [83]. AICD is even more difficult to study, as due to its small size it is rapidly degraded once it is released from the membrane by the insulin degrading enzyme (IDE) [84], that also degrades the Aβ peptide, by the proteasome [85], or by the endosomal/lysosomal system [86]. However, AICD found in the nucleus appears to be more stable, suggesting that AICD involved in signal transduction escapes rapid degradation [87]. Nuclear AICD is stabilized via interaction with Fe65 [88, 89], which accordingly has a dominant function in AICD mediated physiological and pathophysiological processes.

From a structural viewpoint it is evident that the enlarged and unique protein-protein interface coupled with high affinity binding prevents the AICD from degradation. Interestingly, AICD-C31 (starting at Ala665), which is believed to induce apoptosis and is enriched in AD brains [34], fits exactly in length with the AICD part interacting with Fe65-PTB2. Hence, two scenarios comprising a modulating role for Fe65 in AICD-C31 mediated neurotoxicity might be envis‐ aged: (i), under physiological conditions Fe65 protects the AICD from caspase cleavage occurring at Asp664 and might therefore inhibit apoptosis as shown previously [90] and (ii), increased levels of AICD-C31 compete with AICD binding as part of full-length APP and therefore interfere with physiological Fe65 functions including nuclear signaling and traffick‐ ing of APP. In any case, modifying the protein-interacting network around the AICD seems to be a valid target for decreasing neurotoxicity and the treatment of AD.
