Abstract Neurotoxic assemblies of the amyloid β‐protein (Aβ) have been linked strongly to pathogenesis Alzheimer's disease (AD). Here, we sought monitor earliest step in Aβ assembly, creation a folding nucleus, from which oligomeric and fibrillar emanate. To do so, limited proteolysis/mass spectrometry was used identify protease‐resistant segments within monomeric Aβ(1–40) Aβ(1–42). The results revealed 10‐residue, segment, Ala21–Ala30, both peptides. Remarkably, homologous decapeptide,...

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTReactions of propene on zeolite HY catalyst studied by in situ variable temperature solid-state nuclear magnetic resonance spectroscopyJames F. Haw, Benny R. Richardson, Irene S. Oshiro, Noel D. Lazo, and James A. SpeedCite this: J. Am. Chem. Soc. 1989, 111, 6, 2052–2058Publication Date (Print):March 1, 1989Publication History Published online1 May 2002Published inissue 1 March...

The solvent-extractable lipids of human epidermal stratum corneum consist predominantly ceramides. In addition two non-extractable ceramides are chemically bound to the protein. One ceramides, constituting 50% lipids, was previously shown very long chan omega-hydroxyacids in amide linkage with sphingosine. second caramide, which forms 25% contain same hydroxyacids, but sphingoid base neither sphingosine nor phytosphingosine. present study, undefined ceramide by NMR and chemical procedures be...

Folding and self-assembly of the 42-residue amyloid beta-protein (Abeta) are linked to Alzheimer's disease (AD). The 21-30 region Abeta, Abeta(21-30), is resistant proteolysis believed nucleate folding full-length Abeta. conformational space accessible Abeta(21-30) peptide investigated by using replica exchange molecular dynamics simulations in explicit solvent. Conformations belonging global free energy minimum (the "native" state) from simulation good agreement with reported NMR...

Amyloid-β (Aβ) immunotherapy lowers cerebral Aβ and improves cognition in mouse models of Alzheimer's disease (AD). A clinical trial using active immunization with Aβ1–42 was suspended after ∼6% patients developed meningoencephalitis, possibly because a T-cell reaction against Aβ. Nevertheless, beneficial effects were reported antibody responders. Consequently, alternatives are required for safer vaccine. The Aβ1–15 sequence contains the epitope(s) but lacks reactive sites full-length...

Amyloid beta-protein (Abeta) oligomers may be the proximate neurotoxins in Alzheimer's disease (AD). Recently, to elucidate oligomerization pathway, we studied Abeta monomer folding and identified a decapeptide segment of Abeta, (21)Ala-(22)Glu-(23)Asp-(24)Val-(25)Gly-(26)Ser-(27)Asn-(28)Lys-(29)Gly-(30)Ala, within which turn formation appears nucleate folding. The is stabilized by hydrophobic interactions between Val-24 Lys-28 long-range electrostatic either Glu-22 or Asp-23. We...

Oligomeric assemblies of the amyloid β-protein (Aβ) have been implicated in pathogenesis Alzheimer's disease as a primary source neurotoxicity. Recent vitro studies suggested that 10-residue segment, Ala-21-Ala-30, forms turn-like structure nucleates folding full-length Aβ. To gain mechanistic insight, we simulated Aβ(21-30) by using discrete molecular dynamics algorithm and united-atom model incorporating implicit solvent variable electrostatic interaction strength (EIS). We found folds...

Experimental evidence suggests that the folding and aggregation of amyloid beta-protein (Abeta) into oligomers is a key pathogenetic event in Alzheimer's disease. Inhibiting pathologic oligomerization Abeta could be effective prevention treatment Here, using all-atom molecular dynamics simulations explicit solvent, we probe initial stages decapeptide segment Abeta, Abeta(21-30), shown experimentally to nucleate process. In addition, examine homologous containing an amino acid substitution...

The pathologic self-assembly of proteins is associated with typically late-onset disorders such as Alzheimer's disease, Parkinson's and type 2 diabetes. Important mechanistic details the are unknown, but there increasing evidence supporting role transient α-helices in early events. Islet amyloid polypeptide (IAPP) a 37-residue that self-assembles into aggregates toxic to insulin-producing β cells. To elucidate events IAPP, we used limited proteolysis identify an exposed flexible region IAPP...

The self-assembly of insulin to form amyloid fibrils has been widely studied because it is a significant problem in the medical management diabetes and an important model system for investigation formation its inhibition. A few inhibitors fibrillation have identified with potencies that could be higher. Knowledge how these work at molecular level not known but development more potent inhibitors. Here we show rosmarinic acid completely inhibits by dimeric pH 2 60 °C. In contrast other...

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIn situ solid-state NMR study of methanol-to-gasoline chemistry in zeolite HZSM-5Eric J. Munson, Ali A. Kheir, Noel D. Lazo, and James F. HawCite this: Phys. Chem. 1992, 96, 19, 7740–7746Publication Date (Print):September 1, 1992Publication History Published online1 May 2002Published inissue 1 September 1992https://pubs.acs.org/doi/10.1021/j100198a046https://doi.org/10.1021/j100198a046research-articleACS PublicationsRequest reuse permissionsArticle...

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIn situ variable-temperature MAS carbon-13 NMR study of the reactions isobutylene in zeolites HY and HZSM-5Noel D. Lazo, Benny R. Richardson, Paul Schettler, Jeffery L. White, Eric J. Munson, James F. HawCite this: Phys. Chem. 1991, 95, 23, 9420–9425Publication Date (Print):November 1, 1991Publication History Published online1 May 2002Published inissue 1 November...

The interaction of small molecules with the surface amyloid assemblies is important for detection and inhibition formation. Thioflavin T (ThT), a molecular rotor, has been used fibrils over half century. basis simple in that presence fluorescence ThT dramatically enhanced. mechanism this enhancement not well understood but may depend on determination conformation bound to fibril surface. Here, we first use solution-state (1)H NMR show on-off binding insulin correlates fluorescence. We then...

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTryptophan Dynamics and Structural Refinement in a Lipid Bilayer Environment: Solid State NMR of the Gramicidin ChannelW. Hu, N. D. Lazo, T. A. CrossCite this: Biochemistry 1995, 34, 43, 14138–14146Publication Date (Print):October 1, 1995Publication History Published online1 May 2002Published inissue 1 October 1995https://pubs.acs.org/doi/10.1021/bi00043a019https://doi.org/10.1021/bi00043a019research-articleACS PublicationsRequest reuse...

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIn situ carbon-13 solid-state NMR study of the Cu/ZnO/Al2O3 methanol synthesis catalystNoel D. Lazo, David K. Murray, Matthew L. Kieke, and James F. HawCite this: J. Am. Chem. Soc. 1992, 114, 22, 8552–8559Publication Date (Print):October 1, 1992Publication History Published online1 May 2002Published inissue 1 October 1992https://pubs.acs.org/doi/10.1021/ja00048a030https://doi.org/10.1021/ja00048a030research-articleACS PublicationsRequest reuse...

The structure of the 21-30 fragment amyloid beta-protein (Abeta) was investigated by ion mobility mass spectrometry and replica exchange dynamics simulations. Mutations associated with familial Alzheimer's disease (E22G, E22Q, E22K, D23N) Abeta(21-30) were also studied, in order to understand any structural changes that might occur these substitutions. WT peptide shows a bend perpendicular turn backbone which is maintained network D23 hydrogen bonding. Results for mutants show substitutions...

The mechanism for the interaction of thioflavin T (ThT) with amyloid fibrils at molecular level is not known. Here, we used (1) H NMR spectroscopy to determine binding mode ThT on surface from lysozyme and insulin. Relayed rotating-frame Overhauser enhancements in were observed, indicating that orientation orthogonal fibril surface. Importantly, assembly state both surfaces different. On insulin fibrils, oligomeric, as indicated by rapid spin-lattice relaxation rate rotating frame (R1ρ ),...