**Abbreviations**

mediately translocate to the nucleus, where they mediate expressions of certain target genes in association with histone acetyltransferase Tip60 [27]. Besides dephosphorylation of AICD, if phosphorylation of membrane-associated APP is inhibited, non-phosphorylated AICD may also increase. Therefore, it is likely that non-phosphorylated AICD is involved in the

**Figure 6.** Model of APP signaling pathway. The majority of cell membrane-associated APP is phosphorylated within its ICD in neurons. After cleavage of JM domain by α- or β-secretase, AICD is released from the membrane by γ-secretase. Phosphorylated AICD cannot bind to the nuclear adaptor protein Fe65, which is thought to be essential for transloca‐ tion of AICD to the nucleus, and thus cannot translocate to the nucleus. Phosphorylated AICD left in the cytosol is rap‐ idly degraded, probably by the proteasome and/or insulin-degrading enzyme (IDE). On the other hand, dephosphorylated AICD binds to Fe65. Therefore, dephosphorylated AICD/Fe65 complexes immediately translocate to the nucleus, where they meidate up- and downregulation of certain target genes in association with Tip60.

In addition to these possibilities, it is also likely that AICD is ineffective in the normal brain, because almost all AICD is degraded rapidly, and APP signaling cannot be transmitted. However, both AICD and Aβ are overproduced in the AD brain compared to normal brain. Thus, although the majority of AICD is degraded, a small amount of the remaining AICD may play a role in signaling and cause neuron-specific cell death in the AD brain. In addi‐ tion, if the degrading activity of AICD is reduced or lost in the AD brain, APP signaling, which leads to neuron-specific cell death, may be enhanced. Thus, compounds that inhibit translocation of AICD to the nucleus will be good candidates for AD therapy. From this point of view, protein phosphatase inhibitors and chemicals that impair the interaction be‐

γ-Secretase was first identified as a protease that cleaves APP within the transmembrane do‐ main and produces Aβ peptides, which are the main hallmark of AD and are thought to be

onset and progression of AD.

78 Understanding Alzheimer's Disease

tween AICD and Fe65 may be potential ones.

**8. Conclusion**

AD, Alzheimer's disease; Aβ, amyloid-β; APP, amyloid precursor protein; AICD, the intracellular domain of APP; Aph-1, anterior pharynx defective-1; CAA, cerebral amyloid angiopathy; Dll, Delta-like protein Dll1IC, the intracellular domain of Dll1; EGF, epidermal growth factor; FAD, familial AD; Hes, Hairy/Enhancer of split; ICD, intracellular domain;

IDE, insulin-degrading enzyme; JM, juxtamembrane; KPI, Kunitz inhibitor domain; NICD, the intracellular domain of Notch; NCT, nicastrin; NEP, neprilysin; PS, presenilin; Pen-2, PS enhancer-2 protein; RIP, regulated intramembrane proteolysis; RA, all-trans-retinoic acid; TM, transmembrane;

## **Acknowledgments**

Our works described here were supported by the grants-in-aid from the Ministry of Edu‐ cation, Culture, Sports, Science, and Technology of Japan. Some parts of this manuscript have been taken from our publications in Cellular and Molecular Neurobiology Volume 31, Number 6, 887-900 (2011) and in Current Psychopharmacology, Volume 1, Number 2, 155-166 (2012).

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