**1. Introduction**

Talking about Alzheimer's disease (AD) on a biochemical level needs to highlight the molec‐ ular "*corpus delicti*": the amyloid or senile plaques [1]. These plaques are extracellular fibrillar deposits in the cortex and hippocampus mainly composed of a single proteinaceous com‐ pound, the Aβ peptide comprising predominantly 40 or 42 amino acid residues (Aβ40, Aβ42) [2]. The Aβ peptides originate by sequential ectodomain shedding and regulated intramem‐ brane proteolysis (RIP) of the amyloid precursor protein (APP), a type I integral membrane protein highly expressed in neurons including synaptic compartments. The responsible proteases, the famous β- and γ-secretase respectively, have been reviewed in detail and will not be part of this paper [3, 4]. Since the cloning of APP 25 years ago, more than 9,000 publi‐ cations (about one per day!) are listed for this protein in the PubMed database indicating its pivotal position in the amyloid cascade hypothesis [5], which constitutes the widely accepted pathogenic cascade ultimately leading to AD. While some years ago the plaques themselves were thought to be the primary cause of disease, it is nowadays well recognized that soluble Aβ oligomers are responsible for many of the neurotoxic properties causing memory dys‐ function and finally dementia.

Despite intense research efforts AD can so far only be insufficiently treated in a purely symptomatic way and disease-modifying drugs are most wanted but are still not available [6]. In order to get a glimpse of understanding AD pathology at a biochemical level, we therefore have to understand the molecular structure of the key-player APP and its connected protein network. The structure, however, needs to be correlated with the physiological functions and the deregulating mechanisms causing toxicity, cell death, and disease [7, 8]. Bearing this in mind, the simultaneously generated sister peptides of Aβ deserve a major focus, namely the amino-terminal fragment (N-APP286) derived from sAPPβ as a ligand for the death receptor

© 2013 Müller and Wild; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

6 (DR6) [9], and the APP intracellular domain as created by the ε-cut of γ-secretase during the RIP process [3], which is the topic of this paper. We will start by getting the architecture of APP into place.

In terms of three-dimensional structure, only substructures within the large APP ectodo‐ main have been solved as independently folded subdomains. The N-terminal E1 domain is a two-lobe structure consisting of the growth factor like domain (GFLD, residues 18-123) and a copper-binding domain (CuBD, residues 124 to 189), both comprising mixed αβ topologies rigidified by disulfide bridges [11-13]. The E1 domain is followed by a highly acidic, and probably unfolded, stretch of about 100 residues that passes on to the E2 domain (residues 290 to 495), consisting of two coiled-coils connected through a continuous central helix and resembling a spectrin family fold [14]. E1 and E2 domains have been implicated in APP dimerization [14-16], which is reported to be modified by the extracellular matrix [17], and to have significant impact on localization and cleavage events. In addition, dimerization might also involve the TMD region [16]. Besides dimeri‐ zation, APP architecture (and likely function) is also influenced by a series of post-trans‐ lational modifications, mainly by N- and O-glycosylation and phosphorylation [18], which will be discussed in detail below. The reminder of the ectodomain between E2 and the TMD, the so-called juxtamembrane region (residues 496 to 624), is again intrinsi‐ cally disordered based on secondary structure prediction and contains the cleavage sites for the α- and β-secretases. The single TMD is clearly α helical, although with partial propensity in forming β structures. This propensity extends also to the juxtamembrane region with the fatal consequence, that after secretase cleavage the amyloid peptide folds into a β hairpin structure and aggregates to form the toxic oligomers and finally the amyloid fibrils. Finally, the AICD itself is again intrinsically disordered as shown by NMR and CD experiments [19, 20]. Importantly however, this small C-terminal stub has recently been shown to adopt different conformations reflecting its versatile functions. The structure-function relationship of the AICD shall be described in the following.

Structure and Function of the APP Intracellular Domain in Health and Disease

http://dx.doi.org/10.5772/54543

5

When talking about the AICD, a clear distinction has to be made: the function (and probably also the structure) is different for AICD as part of APP at the membrane and for AICD as peptide generated by ε-cleavage of γ-secretase and first described by Passer *et al.* [21]. Within the AICD three sequence motifs have been identified to be of function‐ al relevance. The first one is the 653YTSI sequence, which has been implicated in the baso‐ lateral sorting of APP in polarized MDCK cells [22] and which is reminiscent to the YXXΦ (X: any residue; Φ: aromatic or large hydrophobic residue) consensus motif as ty‐ rosine-based and clathrin-mediated endocytic sorting signal [23]. Indeed, when Tyr653 is mutated to alanine, APP is equally distributed on apical and basolateral membranes in MDCK cells [24]. Somewhat surprisingly, in neurons polarized sorting occurs independ‐ ently of this signal [25]. Subcellular trafficking and neuronal APP sorting is still poorly understood [26] and remains a topic of intense investigation. This first motif contains three phosphorylatable residues (YTS), and it has been reported that at least Thr654 and Ser655 are phosphorylated in the adult rat brain under physiological conditions [27].

**3. Biology of the AICD: Tales of a tail**
