David Teplow on Topline Results: 18 Months of BAN2401 Might Work

COMMENT I'd like to thank Lon Schneider for his thoughtful and informative comments. All I would add is, "Past performance is no guarantee of future failure." dteplow 0 ...

David Teplow on Ion mobility-mass spectrometry reveals a conformational conversion from random assembly to β-sheet in amyloid fibril formation.

COMMENT Filling a Vacuum in Knowledge...With a Vacuum! Ion-Mobility Mass Spectrometry Provides Insight Into Amyloid Protein Assembly In an exciting new paper published in Nature Chemistry, Bleiholder et al. report that the technique of ion mobility-mass ...

David Teplow on Stabilization of neurotoxic Alzheimer amyloid-beta oligomers by protein engineering.

COMMENT Less Is More...When You’re Talking About Aβ Toxicity In 1906, Alois Alzheimer reported an interesting case of dementia at a meeting of the South-West German Society of Alienists (1). Four years later, Emil Kraepelin termed the disease “Alzheimer’s disease ...

David Teplow on Role of amyloid-beta glycine 33 in oligomerization, toxicity, and neuronal plasticity.

COMMENT Sex and the Single Amino Acid—A Devilish Problem In an article published in the 10 June issue of Journal of Neuroscience (1), Harmeier et al. report results of structure-activity studies of the 42-residue form of the amyloid-β protein, Aβ42. The work ...

David Teplow on Initiation and elongation in fibrillation of ALS-linked superoxide dismutase.

COMMENT In this article, Chattopadhyay et al. report results of studies of fibril formation by the amyotrophic lateral sclerosis (ALS)-linked protein superoxide dismutase 1 (SOD1). These studies are important because they show that the phenomena of fibril ...

David Teplow on Aggregation and catabolism of disease-associated intra-Abeta mutations: reduced proteolysis of AbetaA21G by neprilysin.

COMMENT Indigestion and Alzheimer Disease In a number of familial forms of Alzheimer disease (FAD), mutations in the amyloid-β protein (Aβ) precursor, APP, result in single amino acid substitutions in Aβ. These substitutions, named after the ethnicities of the ...

David Teplow on Shaping Up Amyloid Toxicity: Does It Compute?

COMMENT On Computers, Flies, and Alzheimer Disease Two recently published papers address the fundamental question of how amyloid proteins form neurotoxic assemblies (see Luheshi et al., 2007 and Cheon et al., 2007). Pat McCaffrey has written an informative and ...

David Teplow on Atomic structures of amyloid cross-beta spines reveal varied steric zippers.

COMMENT New X-ray Crystallographic Data Reveal Variable Structures in Generic Amyloids Among the “holy grails” in science has been the atomic-resolution determination of amyloid structure. Amyloids, the proteinaceous polymers whose accumulation in the ...

David Teplow on Protein Aggregation In Disease—A New Theory Joins the Fold

COMMENT Cellular homeostasis is an exceedingly complex process. Conceptually, one may consider two regimes within which the phenomenon operates, extra- and intracellular. The extracellular regime requires dynamic responses of the cell to external stimuli. The ...

David Teplow on Functional amyloid formation within mammalian tissue.

COMMENT Functional amyloid and nonfunctional interpretations Fowler et al. report results of studies of the biophysical behavior of the bovine melanosome protein Pmel17 and of the potential role of this protein in melanin biosynthesis. The data strongly support ...

David Teplow on See How They Grow: Structure of Amyloid-β Fibrils

COMMENT The work by Luhrs et al. truly is a tour de force that integrates hydrogen exchange/NMR studies, electron microscopy, thioflavin T-binding, MTT assays, and molecular modeling into studies of the structure of fibrils formed by wild-type Aβ42 and a variety ...

David Teplow on Busting up Plaques—Small Molecules Aided by Protein Heavies

COMMENT In the 29 October issue of Science, Gestwicki, Crabtree, and Graef report results of a beautiful series of experiments testing the hypothesis that small-molecule inhibition of protein assembly can work, as long as the inhibitor isn't small! Gestwicki ...

David Teplow on Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity.

COMMENT Waking up demented: New ideas about anesthesia-induced cognitive impairment In an intriguing paper just published in Anesthesiology, Eckenhoff et al. seek an explanation for the commonly observed transitory, and sometimes persistent, cognitive impairment ...

David Teplow on NSAIDs and Derivatives Keep Transthyretin in Its Place

COMMENT The Enron Collapse and Amyloid Formation What, you might ask, could the Enron collapse have to do with amyloid formation? The answer is, everything, in a sense. If one takes an otherwise stable corporation and begins executing business strategies that ...

David Teplow on New Insights into Fibril Formation

COMMENT An increasing number of neurodegenerative diseases are associated with the formation of amyloid fibrils. Understanding the mechanism of fibril formation thus has obvious clinical value. In addition, knowledge gained in the study of amyloid fibril assembly ...