Journal ArticleDOI
Purification and cloning of amyloid precursor protein beta-secretase from human brain.
Sukanto Sinha,John P. Anderson,Robin Barbour,Guriqbal S. Basi,Russell J. Caccavello,David Davis,Minhtam Doan,Harry F. Dovey,Normand Frigon,Jin Hong,Kirsten L. Jacobson-Croak,Nancy Jewett,Pamela S. Keim,J. Knops,Ivan Lieberburg,Michael Power,Hua Tan,Gwen Tatsuno,Jay Tung,Dale Schenk,Peter Seubert,Susanna Suomensaari,Shuwen Wang,Donald A. Walker,Jun Zhao,Lisa McConlogue,Varghese John +26 more
Reads0
Chats0
TLDR
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 proteinaseread more
Citations
More filters
Journal ArticleDOI
Alzheimer's Disease: Genes, Proteins, and Therapy
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.
Journal ArticleDOI
Pathological roles of MAPK signaling pathways in human diseases
Eunkyung Kim,Eui Ju Choi +1 more
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.
Journal ArticleDOI
The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics.
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.
Journal ArticleDOI
Intracellular amyloid-β in Alzheimer's disease
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.
Journal ArticleDOI
A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline
Thorlakur Jonsson,Jasvinder K. Atwal,Stacy Steinberg,Jon Snaedal,Palmi V. Jonsson,Sigurbjorn Bjornsson,Hreinn Stefansson,Patrick Sulem,Daniel F. Gudbjartsson,Janice A. Maloney,Kwame Hoyte,Amy Gustafson,Yichin Liu,Yanmei Lu,Tushar Bhangale,Robert R. Graham,Johanna Huttenlocher,Gyda Bjornsdottir,Ole A. Andreassen,Erik G. Jönsson,Aarno Palotie,Timothy W. Behrens,Olafur T. Magnusson,Augustine Kong,Unnur Thorsteinsdottir,Unnur Thorsteinsdottir,Ryan J. Watts,Kari Stefansson,Kari Stefansson +28 more
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.
References
More filters
Journal ArticleDOI
On the size of the active site in proteases. I. Papain.
Israel Schechter,Arieh Berger +1 more
Journal ArticleDOI
Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.
Robert Vassar,Brian D. Bennett,Safura Babu-Khan,Steve Kahn,Elizabeth A. Mendiaz,Paul Denis,David B. Teplow,Sandra Ross,Patricia Amarante,Richard Loeloff,Yi Luo,Seth Fisher,Janis Fuller,Steven P. Edenson,Jackson Lile,Mark A. Jarosinski,Anja Leona Biere,Eileen Curran,Teresa L. Burgess,Jean Claude Louis,Frank H. Collins,James J. S. Treanor,Gary Rogers,Martin Citron +23 more
TL;DR: Overexpression of a transmembrane aspartic protease, termed BACE (for beta-site APP-cleaving enzyme) increased the amount of beta-secretase cleavage products, and these were cleaved exactly and only at known beta- secretase positions.
Journal ArticleDOI
Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production
Martin Citron,Tilman Oltersdorf,Christian Haass,Lisa C. Mcconlogue,Albert Y. Hung,Peter Seubert,Carmen Vigo-Pelfrey,Ivan Lieberburg,Dennis J. Selkoe +8 more
TL;DR: C cultured cells which express a β-APP complementary DNA bearing a double mutation found in a Swedish FAD family produce ∼6–8-fold more Aβ than cells expressing normalβ-APP, and this increase is confirmed for elucidating the fundamental mechanism of Alzheimer's disease.
Journal ArticleDOI
A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid.
Michael Mullan,Fiona Crawford,Karin Axelman,Henry Houlden,Lena Lilius,Bengt Winblad,Lars Lannfelt +6 more
TL;DR: A double mutation at codons 670 and 671 (APP 770 transcript) in exon 16 which co–segregates with the disease in two large (probably related) early–onset Alzheimer's disease families from Sweden is identified.
Journal ArticleDOI
Amyloid precursor protein processing and Aβ42 deposition in a transgenic mouse model of Alzheimer disease
Kelly Johnson-Wood,Michael K. Lee,Ruth Motter,Kang Hu,G. Gordon,Robin Barbour,Karen Khan,M. Gordon,H. Tan,Dora Games,I. Lieberburg,Dale Schenk,P. Seubert,Lisa McConlogue +13 more
TL;DR: In this paper, levels of amyloid β-peptide (Aβ) were measured in brain regions of transgenic mice between 4 and 18 months of age, showing that Aβ levels dramatically and predictably increased in brain areas undergoing histochemically confirmed amyloidsosis, most notably in the cortex and hippocampus.
Related Papers (5)
Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.
Robert Vassar,Brian D. Bennett,Safura Babu-Khan,Steve Kahn,Elizabeth A. Mendiaz,Paul Denis,David B. Teplow,Sandra Ross,Patricia Amarante,Richard Loeloff,Yi Luo,Seth Fisher,Janis Fuller,Steven P. Edenson,Jackson Lile,Mark A. Jarosinski,Anja Leona Biere,Eileen Curran,Teresa L. Burgess,Jean Claude Louis,Frank H. Collins,James J. S. Treanor,Gary Rogers,Martin Citron +23 more