Presenilins and γ-secretase: structure, function, and role in Alzheimer Disease

Abstract

Presenilins were first discovered as sites of missense mutations responsible for early-onset Alzheimer disease (AD). The encoded multipass membrane proteins were subsequently found to be the catalytic components of γ-secretases, membrane-embedded aspartyl protease complexes responsible for generating the carboxyl terminus of the amyloid β-protein (Aβ) from the amyloid protein precursor (APP). The protease complex also cleaves a variety of other type I integral membrane proteins, most notably the Notch receptor, signaling from which is involved in many cell differentiation events. Although γ-secretase is a top target for developing disease-modifying AD therapeutics, interference with Notch signaling should be avoided. Compounds that alter Aβ production by γ-secretase without affecting Notch proteolysis and signaling have been identified and are currently at various stages in the drug development pipeline.

Figure 1.

Amino acid sequence, topology, and mutations in presenilin 1. Single amino acid residues that have been found to be substituted by mutations causing familial AD are indicated in red. Exon/intron boundaries, the different transmembrane domains (TM1-TM9), residues (blue) involved in the interaction with amyloid precursor protein (APP), telencephalin (TLN), PEN-2, Nicastrin (NCT), and APH-1 are indicated with brackets. (This figure was adapted from Dillen and Annaert 2006; reprinted, with permission, from Elsevier ©2006. It is based on a figure published on the Alzforum website http://www.alzforum.org/res/com/mut/pre/diagram1.asp.)

Figure 2.

Subunits of the γ-secretase complex and their membrane topologies. Presenilin is proteolytically processed into two fragments during maturation of the complex, an amino-terminal fragment (NTF) and a carboxy-terminal fragment (CTF). The two transmembrane catalytic aspartic acid residues, one in the NTF and one in the CTF, are indicated by D. Other subunits are Nicastrin, APH-1, and PEN-2.

Figure 3.

The role of the γ-secretase complex in biology and disease. Proteolytic processing of certain substrates (e.g., Notch, ErbB4, N-cadherin, E-cadherin) leads to cell signaling. Alternatively, processing of substrates by γ-secretase is simply a means of clearing protein stubs from the membrane. Excessive signaling from the Notch receptor leads to certain forms of cancer, and formation of the amyloid β-protein from its precursor APP by γ-secretase is involved in the pathogenesis of Alzheimer disease.

Figure 4.

Predicted structure in and around the putative catalytic pore of PS1 based on the results of SCAM analysis. (A) Helical wheel model of TMD6 and 7 viewed from the amino terminus. The arrows and asterisks indicate amino acids reactive and nonreactive to biotin-HPDP, respectively, by the SCAM analysis (Tolia et al. 2006). Note that most of the accessible residues cluster on one side, although this domain does not seem to be a classically amphipathic helix. (B) Hypothetical structure around TMD8, 9, and the extreme carboxyl terminus of PS1 in relation to the catalytic pore. Residues labeled by 2-aminoethyl methanethiosulfonate (MTSEA)-biotin by the SCAM analysis (that are accessible to hydrophilic environment; Sato et al. 2008) are shown by a white letter in a black circle.

Figure 5.

γ-Secretase inhibitors recently or currently in clinical trials for the treatment of Alzheimer disease. LY450139 shows little selectivity for APP with respect to the Notch receptor, whereas GSI-953 and BMS-708,163 are clearly selective.