(Cell 170, 443–456.e1–e14; July 27, 2017) Our paper reported that Alzheimer’s disease-linked mutations in Presenilin and the amyloid precursor protein (APP) destabilize interactions between gamma-secretase APP leading to production of longer beta peptides. We have identified two errors Figure 3C manuscript. During preparation final figures, we mislabeled temperature values for PSEN1 mutants. Th...

γ-Secretase generates the peptides of Alzheimer's disease, Aβ(40) and Aβ(42), by cleaving the amyloid precursor protein within its transmembrane domain. γ-Secretase also cleaves numerous other substrates, raising concerns about γ-secretase inhibitor off-target effects. Another important class of drugs, γ-secretase modulators, alter the cleavage site of γ-secretase on amyloid precursor protein, ...

Cerebral deposition of amyloid beta peptide (Abeta) is an early and critical feature of Alzheimer's disease. Abeta generation depends on proteolytic cleavage of the amyloid precursor protein (APP) by two unknown proteases: beta-secretase and gamma-secretase. These proteases are prime therapeutic targets. A transmembrane aspartic protease with all the known characteristics of beta-secretase was ...

BACKGROUND A key player in the development of Alzheimer's disease (AD) is the gamma-secretase complex consisting of at least four components: presenilin, nicastrin, Aph-1 and Pen-2. gamma-Secretase is crucial for the generation of the neurotoxic amyloid beta-peptide (Abeta) but also takes part in the processing of many other substrates. In cell lines, active gamma-secretase has been found to lo...

Many single-transmembrane proteins are sequentially cleaved by ectodomain-shedding α-secretases and the γ-secretase complex, a process called regulated intramembrane proteolysis (RIP). These cleavages are thought to be spatially and temporally separate. In contrast, we provide evidence for a hitherto unrecognized multiprotease complex containing both α- and γ-secretase. ADAM10 (A10), the princi...

The processing of the Amyloid Precursor Protein (APP) is a critical event in the formation of amyloid plaques which are composed of the 4kDa amyloid beta-peptide (Abeta). Processing of APP occurs through a non-amyloidogenic pathway, mediated by initial alpha-secretase cleavage or through an amyloidogenic pathway via sequential cleavage by beta- and gamma-secretase enzymes, which produces Abeta ...

A key event in the pathogenesis of Alzheimer’s disease (AD) is the deposition of senile plaques consisting largely of a peptide known as b-amyloid (Ab) that is derived from the amyloid precursor protein (APP). A proteolytic activity called c-secretase cleaves APP in the transmembrane domain and is required for Ab generation. Aberrant c-secretase cleavage of APP underlies the majority of early o...

γ-Secretase is a four subunit, 19-pass transmembrane enzyme that cleaves amyloid precursor protein (APP), catalyzing the formation of amyloid beta (Aβ) peptides that form amyloid plaques, which contribute to Alzheimer's disease (AD) pathogenesis. γ-Secretase also cleaves Notch, among many other type I transmembrane substrates. Despite its seemingly promiscuous enzymatic capacity, γ-secretase ac...

γ-secretase is an intramembrane protease complex consisting of nicastrin, presenilin-1/2, APH-1a/b, and Pen-2. Hydrolysis of the 99-residue transmembrane fragment of amyloid precursor protein (APP-C99) by γ-secretase produces β-amyloid (Aβ) peptides. Pathogenic mutations in PSEN1 and PSEN2, which encode the catalytic subunit presenilin-1/2 of γ-secretase, lead to familial Alzheimer's disease in...

Amyloidogenic processing of amyloid-β precursor protein (AβPP) is associated with cholesterol- and sphingolipid-rich lipid rafts. Caveolin-1, a raft-residing protein, has been implicated in the pathogenesis of Alzheimer's disease. To determine the role of caveolin-1 in governing γ-secretase-mediated AβPP proteolysis, cellular γ-secretase activity was assessed in response to alteration in caveol...