Author
Kirsten L. Jacobson-Croak
Bio: Kirsten L. Jacobson-Croak is an academic researcher. The author has contributed to research in topics: Protease & Amyloid precursor protein secretase. The author has an hindex of 4, co-authored 6 publications receiving 1824 citations.
Papers
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TL;DR: A membrane-bound enzyme activity that cleaves full-length APP at the β-secretase cleavage site is described and found to be the predominant β-cleavage activity in human brain, and it is found that human brain β- secretase is a new membrane- bound aspartic proteinase.
Abstract: Proteolytic processing of the amyloid precursor protein (APP) generates amyloid β (Aβ) peptide, which is thought to be causal for the pathology and subsequent cognitive decline in Alzheimer's disease Cleavage by β-secretase at the amino terminus of the Aβ peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of β-cleaved soluble APP1, and a corresponding cell-associated carboxy-terminal fragment Cleavage of the C-terminal fragment by γ-secretase(s) leads to the formation of Aβ The pathogenic mutation K670M671 → N670L671 at the β-secretase cleavage site in APP2, which was discovered in a Swedish family with familial Alzheimer's disease, leads to increased β-secretase cleavage of the mutant substrate3 Here we describe a membrane-bound enzyme activity that cleaves full-length APP at the β-secretase cleavage site, and find it to be the predominant β-cleavage activity in human brain We have purified this enzyme activity to homogeneity from human brain using a new substrate analogue inhibitor of the enzyme activity, and show that the purified enzyme has all the properties predicted for β-secretase Cloning and expression of the enzyme reveals that human brain β-secretase is a new membrane-bound aspartic proteinase
1,777 citations
Patent•
07 Jun 1996
TL;DR: In this article, a novel protease capable of cleaving β-amyloid precursor protein (APP) on the amino-terminal side of the β-AMyloid peptide therein is provided.
Abstract: Compositions comprising a novel protease capable of cleaving β-amyloid precursor protein (APP) on the amino-terminal side of the β-amyloid peptide therein are provided. The protease is designated β-secretase. Reaction systems comprising β-secretase may be used in screening assays to monitor β-secretase modulated cleavage of APP and to identify β-secretase inhibitors, wherein the β-secretase is in the presence of a suitable polypeptide substrate and cleavage of the substrate determined in the presence and absence of the test substance. Antibodies are raised against peptides of β-secretase. Pharmaceutical compositions and methods comprise compounds identified by screening assays.
48 citations
Patent•
11 Dec 2001
TL;DR: In this article, a novel protease capable of cleaving a beta-amyloid precursor protein on the amino-terminal side of the peptide therein is described, which is designated beta-secretase.
Abstract: Compositions comprising a novel protease capable of cleaving beta-amyloid precursor protein on the amino-terminal side of the beta-amyloid peptide therein are provided. The protease is designated beta-secretase. The beta-secretase may be used in screening assays to identify beta-secretase inhibitors, or the beta-secretase is combined with a suitable polypeptide substrate and cleavage of the substrate determined in the presence and absence of the test substance.
30 citations
Patent•
02 Apr 1998
TL;DR: In this article, a novel protease capable of cleaving β-amyloid precursor protein on the amino-terminal side of the β-AMyloid peptide therein is provided.
Abstract: Compositions comprising a novel protease capable of cleaving β-amyloid precursor protein on the amino-terminal side of the β-amyloid peptide therein are provided. The protease is designated β-secretase. The β-secretase may be used in screening assays to identify β-secretase inhibitors, or the β-secretase is combined with a suitable polypeptide substrate and cleavage of the substrate determined in the presence and absence of the test substance.
18 citations
Patent•
07 Jun 1996
TL;DR: A nouvelle protease capable de cliver the proteine precurseur de β-amyloide (APP) sur l'extremite N-terminale du peptide β -amyloxide (β-secretase) is described in this paper.
Abstract: Compositions comportant une nouvelle protease capable de cliver la proteine precurseur de β-amyloide (APP) sur l'extremite N-terminale du peptide β-amyloide. La protease est designee sous le nom de β-secretase. Des systemes de reaction faisant appel a la β-secretase peuvent etre utilises dans des methodes de criblage pour surveiller le clivage module par β-secretase de APP et identifier les inhibiteurs de β-secretase: la β-secretase se trouve en presence d'un substrat polypeptidique adapte et le clivage du substrat est determine en presence de cette substance et en l'absence de cette substance. Des anticorps sont suscites contre les peptides de β-secretase. Les compositions pharmaceutiques et les procedes decrits selon l'invention portent egalement sur les composes identifies par les methodes de criblage.
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TL;DR: Evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the beta-amyloid precursor protein by the protease called gamma-secretase has spurred progress toward novel therapeutics and provided discrete biochemical targets for drug screening and development.
Abstract: Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...
5,890 citations
TL;DR: Recent findings on the roles of MAPK signaling pathways in human disorders, focusing on cancer and neurodegenerative diseases including AD, PD, and ALS are summarized.
1,929 citations
TL;DR: It is timely to review the science underpinning the amyloid cascade hypothesis, consider what type of clinical trials will constitute a valid test of this hypothesis and explore whether amyloids-β-directed therapeutics will provide the medicines that are urgently needed by society for treating this devastating disease.
Abstract: The amyloid cascade hypothesis, which posits that the deposition of the amyloid-β peptide in the brain is a central event in Alzheimer's disease pathology, has dominated research for the past twenty years. Several therapeutics that were purported to reduce amyloid-β production or aggregation have failed in Phase III clinical testing, and many others are in various stages of development. Therefore, it is timely to review the science underpinning the amyloid cascade hypothesis, consider what type of clinical trials will constitute a valid test of this hypothesis and explore whether amyloid-β-directed therapeutics will provide the medicines that are urgently needed by society for treating this devastating disease.
1,897 citations
TL;DR: Although the classical view is that Aβ is deposited extracellularly, emerging evidence from transgenic mice and human patients indicates that this peptide can also accumulate intraneuronally, which may contribute to disease progression.
Abstract: The primal role that the amyloid-beta (Abeta) peptide has in the development of Alzheimer's disease is now almost universally accepted. It is also well recognized that Abeta exists in multiple assembly states, which have different physiological or pathophysiological effects. Although the classical view is that Abeta is deposited extracellularly, emerging evidence from transgenic mice and human patients indicates that this peptide can also accumulate intraneuronally, which may contribute to disease progression.
1,660 citations
TL;DR: The strong protective effect of the A673T substitution against Alzheimer’s disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease.
Abstract: The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-β precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.
1,578 citations