Browsing by Author "Selkoe, Dennis"
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The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, Dennis J; Hardy, John (John Wiley and Sons Inc., 2016)Abstract Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 ... -
The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase
Bolduc, David M; Montagna, Daniel R; Seghers, Matthew C; Wolfe, Michael S; Selkoe, Dennis J (eLife Sciences Publications, Ltd, 2016)γ-secretase is responsible for the proteolysis of amyloid precursor protein (APP) into short, aggregation-prone amyloid-beta (Aβ) peptides, which are centrally implicated in the pathogenesis of Alzheimer’s disease (AD). ... -
Aβ Imaging: Feasible, Pertinent, and Vital to Progress in Alzheimer’s Disease
Villemagne, Victor L.; Klunk, William E.; Mathis, Chester A.; Rowe, Christopher C.; Ikonomovic, Milos D.; Ishii, Kenji; Jack, Clifford R.; Jagust, William J.; Koeppe, Robert A.; Lowe, Val J.; Masters, Colin L.; Montine, Thomas J.; Morris, John C.; Nordberg, Agneta; Petersen, Ronald C.; Reiman, Eric M.; Van Laere, Koen; Drzezga, Alexander; Brooks, David J.; Hyman, Bradley Theodore; Johnson, Keith Alan; Selkoe, Dennis J.; Sperling, Reisa Anne; Weiner, Michael W. (Springer-Verlag, 2012) -
Designed Inhibitors of Insulin-Degrading Enzyme Regulate the Catabolism and Activity of Insulin
Leissring, Malcolm A.; Malito, Enrico; Hedouin, Sabrine; Reinstatler, Lael; Sahara, Tomoko; Abdul-Hay, Samer O.; Choudhry, Shakeel; Maharvi, Ghulam M.; Fauq, Abdul H.; Huzarska, Malwina; May, Philip S.; Logan, Todd P.; Turk, Benjamin E.; Manolopoulou, Marika; Tang, Wei-Jen; Stein, Ross L.; Choi, Sungwoon; Cantley, Lewis C.; Cuny, Gregory Douglas; Selkoe, Dennis J. (Public Library of Science, 2010)Background: Insulin is a vital peptide hormone that is a central regulator of glucose homeostasis, and impairments in insulin signaling cause diabetes mellitus. In principle, it should be possible to enhance the activity ... -
A highly sensitive novel immunoassay specifically detects low levels of soluble Aβ oligomers in human cerebrospinal fluid
Yang, Ting; O’Malley, Tiernan T; Kanmert, Daniel; Jerecic, Jasna; Zieske, Lynn R; Zetterberg, Henrik; Hyman, Bradley T; Walsh, Dominic M; Selkoe, Dennis J (BioMed Central, 2015)Introduction: Amyloid β-protein oligomers play a key role in Alzheimer’s disease (AD), but well-validated assays that routinely detect them in cerebrospinal fluid (CSF) are just emerging. We sought to confirm and extend a ... -
Identification of β-Secretase (BACE1) Substrates Using Quantitative Proteomics
Elias, Joshua E.; Maas, Stefan; Gygi, Steven P.; Selkoe, Dennis J.; Hemming, Matthew Louis (Public Library of Science, 2009)β-site APP cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease with a lumenal active site that sheds the ectodomains of membrane proteins through juxtamembrane proteolysis. BACE1 has been studied principally for ... -
N-Alpha-Acetylation of α-Synuclein Increases Its Helical Folding Propensity, GM1 Binding Specificity and Resistance to Aggregation
Bartels, Tim; Kim, Nora C.; Luth, Eric S.; Selkoe, Dennis J. (Public Library of Science, 2014)A switch in the conformational properties of α-synuclein (αS) is hypothesized to be a key step in the pathogenic mechanism of Parkinson’s disease (PD). Whereas the beta-sheet-rich state of αS has long been associated with ... -
A New Method for Quantitative Immunoblotting of Endogenous α-Synuclein
Newman, Andrew J.; Selkoe, Dennis; Dettmer, Ulf (Public Library of Science, 2013)β-Sheet-rich aggregates of α-synuclein (αSyn) are the hallmark neuropathology of Parkinson’s disease and related synucleinopathies, whereas the principal native structure of αSyn in healthy cells - unfolded monomer or ... -
Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation
Dettmer, Ulf; Newman, Andrew J.; Soldner, Frank; Luth, Eric S.; Kim, Nora C.; von Saucken, Victoria E.; Sanderson, John B.; Jaenisch, Rudolf; Bartels, Tim; Selkoe, Dennis (Nature Pub. Group, 2015)β-Sheet-rich α-synuclein (αS) aggregates characterize Parkinson's disease (PD). αS was long believed to be a natively unfolded monomer, but recent work suggests it also occurs in α-helix-rich tetramers. Crosslinking traps ... -
Pen-2 Is Essential for γ-Secretase Complex Stability and Trafficking but Partially Dispensable for Endoproteolysis
Holmes, Oliver; Paturi, Swetha; Selkoe, Dennis J.; Wolfe, Michael S. (American Chemical Society, 2014)The 19-transmembrane γ-secretase complex generates the amyloid β-peptide of Alzheimer’s disease by intramembrane proteolysis of the β-amyloid precursor protein. This complex is comprised of presenilin, Aph1, nicastrin, and ... -
Physical and functional interaction between the α- and γ-secretases: A new model of regulated intramembrane proteolysis
Chen, Allen C.; Kim, Sumin; Shepardson, Nina; Patel, Sarvagna; Hong, Soyon; Selkoe, Dennis J. (The Rockefeller University Press, 2015)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 ... -
Physiological and Pathological Characterization of Alpha-Synuclein Oligomers
Luth, Eric Sloan (2014-06-06)α-Synuclein (αSyn) is highly abundant cytosolic protein whose conversion into insoluble fibrils is a pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Despite decades of research, fundamental ... -
Probing the In Vivo Economy of Amyloid Beta-Protein during the Development of Alzheimer's Disease-Type Pathology
Hong, Soyon Youngae (2012-09-17)Despite intense therapeutic and diagnostic focus on dyshomeostasis of amyloid \(\beta\)-peptide \((A\beta)\) in Alzheimer’s disease (AD), we still lack insight into the in vivo economy of \(A\beta\) in the normal and ... -
Proteomic Profiling of γ-Secretase Substrates and Mapping of Substrate Requirements
Hemming, Matthew Louis; Elias, Joshua E; Gygi, Steven P.; Selkoe, Dennis J. (Public Library of Science, 2008)The presenilin/γ-secretase complex, an unusual intramembrane aspartyl protease, plays an essential role in cellular signaling and membrane protein turnover. Its ability to liberate numerous intracellular signaling proteins ... -
Purification of α-Synuclein from Human Brain Reveals an Instability of Endogenous Multimers as the Protein Approaches Purity
Luth, Eric S.; Bartels, Tim; Dettmer, Ulf; Kim, Nora C.; Selkoe, Dennis J. (American Chemical Society, 2014)Despite two decades of research, the structure–function relationships of endogenous, physiological forms of α-synuclein (αSyn) are not well understood. Most in vitro studies of this Parkinson’s disease-related protein have ... -
Reducing Amyloid Plaque Burden via Ex Vivo Gene Delivery of an Aβ-Degrading Protease: A Novel Therapeutic Approach to Alzheimer Disease
Hemming, Matthew Louis; Patterson, Michaela; Reske-Nielsen, Casper; Lin, Ling; Isacson, Ole Stefan; Selkoe, Dennis J. (Public Library of Science, 2007)Background: Understanding the mechanisms of amyloid-β protein (Aβ) production and clearance in the brain has been essential to elucidating the etiology of Alzheimer disease (AD). Chronically decreasing brain Aβ levels is ... -
Regulation of the Proteolytic Processing and Function of Amyloid Precursor Protein by Candidate Ligands
Rice, Heather Caroline (2013-08-28)Despite intense interest in the proteolysis of Amyloid Precursor Protein (APP) in Alzheimer’s disease (AD), how the normal processing and function of this type I receptor-like glycoprotein is regulated remains ill-defined. ... -
Secreted Amyloid β-Proteins in a Cell Culture Model Include N-Terminally Extended Peptides That Impair Synaptic Plasticity
Welzel, Alfred T.; Maggio, John E.; Shankar, Ganesh M.; Walker, Donald E.; Ostaszewski, Beth L.; Li, Shaomin; Klyubin, Igor; Rowan, Michael J.; Seubert, Peter; Walsh, Dominic M.; Selkoe, Dennis J. (American Chemical Society, 2014)Evidence for a central role of amyloid β-protein (Aβ) in the genesis of Alzheimer’s disease (AD) has led to advanced human trials of Aβ-lowering agents. The “amyloid hypothesis” of AD postulates deleterious effects of ... -
Secreted APP Regulates the Function of Full-Length APP in Neurite Outgrowth Through Interaction With Integrin Beta1
Young-Pearse, Tracy L; Chen, Allen Ching-Way; Chang, Rui; Marquez, Cesar; Selkoe, Dennis J. (BioMed Central, 2008)Background: β-Amyloid precursor protein (APP) has been reported to play a role in the outgrowth of neurites from cultured neurons. Both cell-surface APP and its soluble, ectodomain cleavage product (APPs-α) have been ... -
Small-Molecule Activators of Insulin-Degrading Enzyme Discovered through High-Throughput Compound Screening
Cabrol, Christelle; Huzarska, Malwina A.; Dinolfo, Christopher; Rodriguez, Maria C.; Reinstatler, Lael; Ni, Jake; Yeh, Li-An; Stein, Ross L.; Leissring, Malcolm A.; Cuny, Gregory Douglas; Selkoe, Dennis J. (Public Library of Science, 2009)Background: Hypocatabolism of the amyloid β-protein (Aβ) by insulin-degrading enzyme (IDE) is implicated in the pathogenesis of Alzheimer disease (AD), making pharmacological activation of IDE an attractive therapeutic ...