Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein

Strooper, Bart De; Säftig, Paul; Craessaerts, Katleen; Vanderstichele, Hugo; Guhde, Gundula; Annaert, Wim; Figura, Kurt Von; Leuven, Fred Van

doi:10.1038/34910

Cited by 1,718 publications

(1,256 citation statements)

References 28 publications

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“…Conditioned media was then harvested for Aβ ELISA at the same time that cell lysates were harvested for AICD-GVP ELISA or Luciferase assay. Consistent with previous reports [10, 11, 13], the Aβ ELISA demonstrated that PS1 generates approximately five-fold more Aβ than PS2 (Fig. 1B ), thereby validating our substrate and cell-based system.…”

Section: Resultssupporting

confidence: 92%

“…In vitro cellular and biochemical studies [8-12], as well as in vivo loss of function studies [13-18] have demonstrated that PS1-containing complexes generate significantly more Aβ peptide from the APP substrate than PS2-containing complexes. As a result, the majority of studies have focused on PS1 in their efforts to better understand γ-secretase biology and to identify ways to inhibit or modulate its activity for the treatment of AD.…”

Section: Introductionmentioning

confidence: 99%

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Evidence that Enzyme Processivity Mediates Differential Aβ Production by PS1 and PS2

Pintchovski¹,

Basi²

2013

Current Alzheimer Research

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The γ-secretase complex cleaves the carboxy-terminal 99 residue (C99) fragment of the amyloid precursor protein (APP) to generate the amyloid-β (Aβ) peptide. The catalytic activity of this complex is mediated either by the presenilin-1 (PS1) or the presenilin-2 (PS2) subunit. In vitro and in vivo studies have demonstrated that PS1-containing complexes generate more total Aβ product than PS2-containing complexes, indicating greater cleavage activity by PS1-containing γ-secretase complexes at the APP γ-site. However, it remains untested whether γ-secretase cleavage at the APP ε-site, which precedes γ-site cleavage and produces the physiologically active APP intracellular domain (AICD), follows the same rule. Using a novel Swedish APP-GVP substrate to facilitate the parallel detection of Aβ and AICD products from PS1-/-/PS2-/- cells co-transfected with either PS1 or PS2, we observed that while PS1 generates more total Aβ product than PS2, consistent with published reports, PS1 and PS2 unexpectedly generate equal amounts of AICD product. We also observed that PS1 and PS2 produce equivalent amounts of Notch intracellular domain (NICD), indicating equal cleavage activity at the Notch S3-site (the corollary of the APP ε-site). Our findings suggest that processivity differences between PS1 and PS2 underlie the differential production of Aβ peptide. Taken together these findings offer novel insights into γ-secretase biology and have important implications for therapeutically targeting γ-secretase

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Evidence that Enzyme Processivity Mediates Differential Aβ Production by PS1 and PS2

Pintchovski¹,

Basi²

2013

Current Alzheimer Research

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“…PS1 is a constituent of the γ‐secretase complex that cleaves the C terminal fragment of APP generated by β‐secretase (CTF‐β) to produce Aβ (De Strooper et al , 1998). PS1 mutations cause the majority of FAD cases (Karch et al , 2014).…”

Section: First‐generation Mouse Modelsmentioning

confidence: 99%

APP mouse models for Alzheimer's disease preclinical studies

et al. 2017

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Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first‐generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant amyloid precursor protein (APP), or APP and presenilin (PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD. Second‐generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene. These mice show Aβ accumulation without phenotypes related to overexpression but are not yet a clinical recapitulation of human AD. In this review, we evaluate different APP mouse models of AD, and review recent studies using the second‐generation mice. We advise AD researchers to consider the comparative strengths and limitations of each model against the scientific and therapeutic goal of a prospective preclinical study.

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“…Even more remarkable is the broad array of cellular networks that intramembrane proteases have come to regulate. Intensively studied is γ-secretase, an aspartyl intramembrane protease that releases signaling domains from the membrane, including the intracellular domains of the Notch receptor and the amyloid-β precursor protein (APP) implicated in Alzheimer's disease (De Strooper et al, 1998, 1999; Wolfe et al, 1999). Homologous signal peptide peptidases function in immunity by liberating signaling domains of TNFα and FasL (Fluhrer et al, 2006; Friedmann et al, 2006; Kirkin et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics

Moin

Urban

2012

eLife

119

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Rhomboid proteases reside within cellular membranes, but the advantage of this unusual environment is unclear. We discovered membrane immersion allows substrates to be identified in a fundamentally-different way, based initially upon exposing ‘masked’ conformational dynamics of transmembrane segments rather than sequence-specific binding. EPR and CD spectroscopy revealed that the membrane restrains rhomboid gate and substrate conformation to limit proteolysis. True substrates evolved intrinsically-unstable transmembrane helices that both become unstructured when not supported by the membrane, and facilitate partitioning into the hydrophilic, active-site environment. Accordingly, manipulating substrate and gate dynamics in living cells shifted cleavage sites in a manner incompatible with extended sequence binding, but correlated with a membrane-and-helix-exit propensity scale. Moreover, cleavage of diverse non-substrates was provoked by single-residue changes that destabilize transmembrane helices. Membrane immersion thus bestows rhomboid proteases with the ability to identify substrates primarily based on reading their intrinsic transmembrane dynamics.DOI: http://dx.doi.org/10.7554/eLife.00173.001

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Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein

Cited by 1,718 publications

References 28 publications

Evidence that Enzyme Processivity Mediates Differential Aβ Production by PS1 and PS2

Evidence that Enzyme Processivity Mediates Differential Aβ Production by PS1 and PS2

APP mouse models for Alzheimer's disease preclinical studies

Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics

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