**Pathogenesis**

**Chapter 1**

**Structure and Function of**

Ulrike Müller and Klemens Wild

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

function and finally dementia.

**1. Introduction**

Additional information is available at the end of the chapter

**the APP Intracellular Domain in Health and Disease**

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‐

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

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© 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,
