Potential Use of γ-Secretase Modulators in the Treatment of Alzheimer Disease

Figure 1. γ-Secretase processing of amyloid precursor protein C-terminal fragments (CTFs). A cartoon illustration shows the various subunits of the γ-secretase enzyme complex performing a number of different putative γ-secretase–mediated proteolytic activities. Assembly and maturation of the γ-secretase enzyme begins with the formation of a binary complex between nicastrin and anterior pharynx defective 1 (Aph-1). Presenilin (PS) binds to the nicastrin/Aph-1 complex to form an inactive trimeric complex. The PS N-terminal fragment (NTF) and the PS-CTF collectively harbor the catalytic center of γ-secretase, which requires binding of presenilin enhancer 2 (Pen-2) for the endoproteolysis of PS into the PS-NTF and the PS-CTF, rendering activation of γ-secretase. The active γ-secretase enzyme can cleave the amyloid precursor protein CTF at numerous sites, yielding a host of peptide products (amyloid precursor protein intracellular domain [AICD], β-amyloid (Aβ) 1-42, Aβ1-40, Aβ1-39, Aβ1-38, and Aβ1-37). The relative size of the curved arrows at the γ sites indicates the relative use of each processing site. The ϵ cleavages (larger curved arrows at amino acids 48 and 49 of the 99–amino acid–long amyloid precursor protein CTF) generate the AICDs, which remain inside the cell (as indicated by the direction of the right arrow) and may actually travel to the nucleus, while the various Aβ peptides are released extracellularly (as indicated by the direction of the left arrow) immediately on cleavage by γ-secretase within the membrane. The different colors correspond to the different proteolytic processing products.

Figure 2. Semiquantitative estimation of the outcome in healthy individuals (A) and in individuals harboring early-onset familial Alzheimer disease (EOFAD)–linked mutations before (B) and after receiving either a γ-secretase modulator (GSM) (C) or a γ-secretase inhibitor (GSI) (D). The graphs represent shifts in the different forms of β-amyloid (Aβ) that result from processing by normal (wild-type) γ-secretase, mutations in the presenilin component of γ-secretase that result in EOFAD, and the effects of treatment with GSIs or GSMs. The heights (ordinate) and lengths (abscissa) of each Aβ peptide variant correspond to the relative abundance and the number of amino acids, respectively. The GSMs elicit a unique bidirectional biomarker profile with respect to their effects on Aβ peptide variants (decreasing Aβ42 and Aβ40 levels, while increasing Aβ38 and Aβ37 levels). AU indicates arbitrary units; CTFs, C-terminal fragments.