Journal ArticleDOI
Membrane anchored and lipid raft targeted β-secretase inhibitors for Alzheimer's disease therapy.
Reads0
Chats0
TLDR
It is proposed that membrane-anchoring of β-secretase inhibitors would render them endocytosis-competent thereby enabling the inhibitors to reach these compartments that harbor active β- secretase and could be applied for many membrane targets that are localized either at the plasma membrane or in the endocytic compartments.Abstract:
β-secretase, a key enzyme involved in amyloid-β generation, is an attractive candidate for Alzheimer's disease therapy. Transition-state inhibitors of β-secretase are designed to achieve specificity. However, these inhibitors bind only to the active conformation of the enzyme and as the active β-secretase is sequestered in subcellular compartments, new strategies have to be implemented. We propose that membrane-anchoring of β-secretase inhibitors would render them endocytosis-competent thereby enabling the inhibitors to reach these compartments that harbor active β-secretase. By choosing cholesterol as a membrane anchor, we also enrich the inhibitor in lipid rafts where much of the β-secretase is present. In addition, membrane-anchoring of soluble inhibitors reduces the dimensionality of the inhibitor and consequently increases the inhibitor concentration at the target membrane plane. Such inhibitors have great potential in terms of substrate selectivity and reduced side effects. Not only for β-secretase, this strategy could be applied for many membrane targets that are localized either at the plasma membrane or in the endocytic compartments.read more
Citations
More filters
Journal ArticleDOI
Membrane trafficking pathways in Alzheimer's disease.
Lawrence Rajendran,Wim Annaert +1 more
TL;DR: An update of the current appraisal on how membrane trafficking may play an important role in the pathogenesis of the disease and how this could be exploited for effective therapy is discussed.
Journal ArticleDOI
Alzheimer’s disease: relevant molecular and physiopathological events affecting amyloid-β brain balance and the putative role of PPARs
Juan M. Zolezzi,Sussy Bastías-Candia,Manuel J. Santos,Nibaldo C. Inestrosa,Nibaldo C. Inestrosa,Nibaldo C. Inestrosa +5 more
TL;DR: The present review revise the current knowledge regarding the molecular aspects of Aβ production and clearance and provide a physiological context that gives a more complete view of this issue.
Journal ArticleDOI
Retromers in Alzheimer's disease.
TL;DR: The role of retromers in the amyloidogenic processing of APP and their pathogenic role in AD are reviewed.
Journal ArticleDOI
Regulation of cerebral cholesterol metabolism in Alzheimer disease.
Allison B. Reiss,Iryna Voloshyna +1 more
TL;DR: This review summarizes the current state of knowledge of the influence of cholesterol and lipid pathways in AD pathogenesis in vitro and in vivo and indicates multiple lines of evidence indicate a role for cholesterol in AD.
Journal ArticleDOI
Monitoring β-secretase activity in living cells with a membrane-anchored FRET probe.
TL;DR: Because evidence of Aβ and its associated toxicity are widespread in the post-mortem AD brain, preventing Aβ formation has been a suggested strategy for potential therapeutic intervention, but in order to develop effective drugs, advanced chemical tools are needed to efficiently elucidate the proteins involved in Aβ generation, and measure how they are affected under various conditions.
References
More filters
Journal ArticleDOI
Functional rafts in cell membranes
Kai Simons,Elina Ikonen +1 more
TL;DR: A new aspect of cell membrane structure is presented, based on the dynamic clustering of sphingolipids and cholesterol to form rafts that move within the fluid bilayer that function as platforms for the attachment of proteins when membranes are moved around inside the cell and during signal transduction.
Journal ArticleDOI
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.
Christian Haass,Dennis J. Selkoe +1 more
TL;DR: Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.
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
Lipid Rafts As a Membrane-Organizing Principle
Daniel Lingwood,Kai Simons +1 more
TL;DR: The evidence for how this principle combines the potential for sphingolipid-cholesterol self-assembly with protein specificity to selectively focus membrane bioactivity is reviewed.
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
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.