Alzheimer's disease (AD) is the most frequent form of progressive dementia, occurring predominantly in the elderly population. AD is characterized by the presence of amyloid plaques, extensive neuronal death and shrinkage of the brain. It is increasingly accepted that the neurotoxic β-amyloid or A4 peptide (β/A4) is responsible for compromising neuronal functions and triggering cell death. The peptide is derived from the cleavage of the amyloid precursor protein (APP) and is the main constituent of the amyloid plaques. APP belongs to a wider family of APP-like proteins (APLPs) that include APLP1 and APLP2 in mammals (see <PDOC00204>). These proteins exhibit functional redundancy to some degree and can undergo cleavage, but only APP cleavage gives rise to the β/A4 peptide. APP and APLPs are type-I transmembrane proteins with a large extracellular portion, which can be structurally and functionally subdivided into several domains. At the N-terminus is a cysteine-rich region, termed E1, consisting of the growth factor like domain (GFLD), which binds heparin and can stimulate neurite outgrowth, and a copper-binding domain (CuBD) that binds Cu and Zn. The E1 domain is followed by an acidic-rich region of sequence, a Kunitz-type protease inhibitor (KPI) domain (see <PDOC00252>) and an OX2 domain. Following these domains is a glycosylated domain referred to as E2, a region predicted to adopt no regular secondary structure and the transmembrane region. The C-terminal cytoplasmic tail may be involved in various cellular functions, such as transcription signaling, through interaction with a multitude of proteins. Homo- and heterodimerization of APP and APLPs, which are enhanced by heparan sulfate binding, may play a role in signal transduction and cell adhesion.

The E1 domain functions as a rigid functional entity. Two E1 entities dimerize upon their interaction with heparin, requiring 8-12 sugar rings to form the heparin-bridged E1 dimer. The two subdomains, GFLD and CuBD, interact tightly in a pH-dependent manner via an evolutionarily conserved interface area (see <PDB:3KTM>). The highly conserved, well-defined interdomain linker does not adopt any standard secondary structure but connects both subdomains like a zipper and contributes to the mostly hydrophobic interdomain interface area [1,2]. The slightly larger GFLD subdomain consists of a central antiparallel β-sheet, one α-helix, and a short two-stranded β-sheet, cross-connected by three disulfide bridges (see <PDB:1MWP>) [3]. The 65-residue CuBD subdomain is defined by conserved histidine residues and consists of a central three-stranded antiparallel β-sheet and a long α-helix, catenated by three additional disulfide bridges (see <PDB:2FK2>) [4,5,6].

The E2 domain forms an antiparallel dimer. E2 dimerization is a dynamic and reversible process and heparin binding to E2 shifts the association-dissociation equilibrium in favor of dimer. The structure of E2 consists of two coiled-coil substructures connected through a continuous helix and bears an unexpected resemblance to the spectrin family of protein structure (see <PDB:3NYL>). The E2 contains a high affinity heparin binding site [7,8,9].

We have derived two patterns specific to these proteins, the first one is a perfectly conserved octapeptide located in the CuBD domain; the second is a conserved octapeptide located at the C-terminal end of the cytoplasmic domain. We also developed two profiles covering respectively the entire E1 and E2 domains.