Making the final cut: pathogenic amyloid-β peptide generation by γ-secretase

Abstract

Alzheimer´s disease (AD) is a devastating neurodegenerative disease of the elderly population. Genetic evidence strongly suggests that aberrant generation and/or clearance of the neurotoxic amyloid-β peptide (Aβ) is triggering the disease. Aβ is generated from the amyloid precursor protein (APP) by the sequential cleavages of β- and γ-secretase. The latter cleavage by γ-secretase, a unique and fascinating four-component protease complex, occurs in the APP transmembrane domain thereby releasing Aβ species of 37-43 amino acids in length including the longer, highly pathogenic peptides Aβ42 and Aβ43. The lack of a precise understanding of Aβ generation as well as of the functions of other γ-secretase substrates has been one factor underlying the disappointing failure of γ-secretase inhibitors in clinical trials, but on the other side also been a major driving force for structural and in depth mechanistic studies on this key AD drug target in the past few years. Here we review recent breakthroughs in our understanding of how the γ-secretase complex recognizes substrates, of how it binds and processes β-secretase cleaved APP into different Aβ species, as well as the progress made on a question of outstanding interest, namely how clinical AD mutations in the catalytic subunit presenilin and the γ-secretase cleavage region of APP lead to relative increases of Aβ42/43. Finally, we discuss how the knowledge emerging from these studies could be used to therapeutically target this enzyme in a safe way.

Toward the Characterization of DAPT Interactions with γ‐Secretase

“…[29] Those results and further photolabeling experiments suggested that DAPT inhibition is distinct from TSA, but both compete for the active site and exhibit partially overlapped binding pockets. [30][31][32] In agreement with previouso bservations, our proposed DAPT binding pose shows that this compound is in close proximity to the active site but does not interactw ith the catalytic aspartic acids. [26] Similar behavior was found for the GSI avagacestat (BMS-708163), which binds within TM2, TM3, TM5, and TM7 of PS1 component without interacting with the catalytic dyad.…”

Aβ43‐producing PS1 FAD mutants cause altered substrate interactions and respond to γ‐secretase modulation

“…For these mutants, the processivity changes appear also to be associated with a stronger loss of function in the esite cleavage of C99 [16,17,19]. PS1 and PS2 normally undergo presenilin endoproteolysis [21] in which they are autoproteolytically cleaved into N-and C-terminal fragments (NTF, CTF) [2]; however, in a few FAD mutants, this step is blocked or impaired. PS1 and PS2 normally undergo presenilin endoproteolysis [21] in which they are autoproteolytically cleaved into N-and C-terminal fragments (NTF, CTF) [2]; however, in a few FAD mutants, this step is blocked or impaired.…”

“…However, since deficiencies in the initial e-site cleavage are largely compensated by the unaffected wt PS1 and PS2 alleles in human FAD brain, while pathogenic Ab ratios persist [20], it is unlikely that FAD mutant c-secretases show an impact on signaling functions. PS1 and PS2 normally undergo presenilin endoproteolysis [21] in which they are autoproteolytically cleaved into N-and C-terminal fragments (NTF, CTF) [2]; however, in a few FAD mutants, this step is blocked or impaired. This is also and prominently seen for the PS1 R278I and PS1 L435F mutants [16][17][18][19] indicating that their strong deficiency in presenilin endoproteolysis may contribute to their loss in processivity thereby resulting in the formation of longer Ab43 species.…”

Uncovering the Binding Mode of γ-Secretase Inhibitors

“…The intra-membrane cleaving hetero-tetramer γ-secretase (GSEC) processes the C-terminal fragment of the amyloid precursor protein (APP), C99. [1][2][3][4][5][6] Since some of the resulting cleavage products are strongly linked to Alzheimer's disease (AD), GSEC is at the focus of many drug-design research efforts. [7][8][9][10][11] Ultimately, one wishes to control or modulate C99 processing to prevent the progression of, or even cure, AD.…”