23 research outputs found
Destruxin E Decreases Beta-Amyloid Generation by Reducing Colocalization of Beta-Amyloid-Cleaving Enzyme 1 and Beta-Amyloid Protein Precursor
Alzheimer-disease-associated beta-amyloid (A beta) is produced by sequential endoproteolysis of beta-amyloid protein precursor (beta APP): the extracellular portion is shed by cleavage in the juxtamembrane region by beta-amyloid-cleaving enzyme (BACE)/beta-secretase, after which it is cleaved by presenilin (PS)/gamma-secretase near the middle of the transmembrane domain. Thus, inhibition of either of the secretases reduces A beta generation and is a fundamental strategy for the development of drugs to prevent Alzheimer disease. However, it is not clear how small compounds reduce A beta production without inhibition of the secretases. Such compounds are expected to avoid some of the side effects of secretase inhibitors. Here, we report that destruxin E (Dx-E), a natural cyclic hexadepsipeptide, reduces A beta generation without affecting BACE or PS/gamma-secretase activity. In agreement with this, Dx-E did not inhibit Notch signaling. We found that Dx-E decreases colocalization of BACE1 and beta APP, which reduces beta-cleavage of beta APP. Therefore, the data demonstrate that Dx-E represents a novel A beta-reducing process which could have fewer side effects than secretase inhibitors. Copyright (C) 2009 S. Karger AG, Base
Synthesis of High-molecular-weight Head-to-tail-type Poly(3-substituted-thiophene)s by Cross-coupling Polycondensation with [CpNiCl(NHC)] as a Catalyst
CSF Tau phosphorylation at Thr205 is associated with loss of white matter integrity in autosomal dominant Alzheimer disease
BACKGROUND: Hyperphosphorylation of tau leads to conformational changes that destabilize microtubules and hinder axonal transport in Alzheimer\u27s disease (AD). However, it remains unknown whether white matter (WM) decline due to AD is associated with specific Tau phosphorylation site(s).
METHODS: In autosomal dominant AD (ADAD) mutation carriers (MC) and non-carriers (NC) we compared cerebrospinal fluid (CSF) phosphorylation at tau sites (pT217, pT181, pS202, and pT205) and total tau with WM measures, as derived from diffusion tensor imaging (DTI), and cognition. A WM composite metric, derived from a principal component analysis, was used to identify spatial decline seen in ADAD.
RESULTS: The WM composite explained over 70% of the variance in MC. WM regions that strongly contributed to the spatial topography were located in callosal and cingulate regions. Loss of integrity within the WM composite was strongly associated with AD progression in MC as defined by the estimated years to onset (EYO) and cognitive decline. A linear regression demonstrated that amyloid, gray matter atrophy and phosphorylation at CSF tau site pT205 each uniquely explained a reduction in the WM composite within MC that was independent of vascular changes (white matter hyperintensities), and age. Hyperphosphorylation of CSF tau at other sites and total tau did not significantly predict WM composite loss.
CONCLUSIONS: We identified a site-specific relationship between CSF phosphorylated tau and WM decline within MC. The presence of both amyloid deposition and Tau phosphorylation at pT205 were associated with WM composite loss. These findings highlight a primary AD-specific mechanism for WM dysfunction that is tightly coupled to symptom manifestation and cognitive decline
ダイガクセイ ノ ウンドウ ・ スポーツ カツドウ ト セイカツ マンゾク ド ノ カンレン ニ カンスル シツテキ ケンキュウ ( 1 ) : 「 ケイゾク 」 ト 「 サイ シャカイカ 」 ノ シテン カラ
Nickel(II)-Catalyzed Cross-Coupling Polycondensation of Thiophenes via C–S Bond Cleavage
Cross-coupling polycondensation of
thiophene derivatives occurs
via C–S bond cleavage in the presence of a nickel catalyst.
Head to tail type (HT) regioregular poly(3-hexylthiophene) is obtained
by a nickel(II)-catalyzed deprotonative C–H functionalization
polycondensation of 2-(phenylsulfonyl)-3-hexylthiophene with stoichiometric
TMPMgCl·LiCl or with the catalytic secondary amine/RMgX. Debrominative
Grignard metathesis (GRIM) polymerization with 5-bromo-2-(phenylsulfonyl)-3-hexylthiophene
also proceeds by the catalysis of the nickel(II) complex to afford
the corresponding polythiophene
pH Switching That Crosses over the Isoelectric Point (pI) Can Improve the Entrapment of Proteins within Giant Liposomes by Enhancing Protein–Membrane Interaction
The ability to encapsulate various
molecules including proteins
within giant liposomes is needed for studies on model cell membranes
and artificial cells. In this report, we demonstrate how to improve
the efficiency of protein entrapment with the gentle hydration (natural
swelling) method, which is a well-known protocol for the preparation
of giant liposomes. We found that when the initial pH of a solution
was kept below the pI of a target protein during hydration and then
changed to above the pI, the protein could be entrapped more efficiently
compared to the sample that was kept at above the pI during the hydration.
An examination of the ratio of the mass of entrapped protein to the
moles of phospholipid in liposomes (dioleoylphosphatidylcholine (DOPC)/dioleoylphosphatidylglycerol
(DOPG)) indicated that entrapment of target proteins like bovine serum
albumin, myoglobin, and lysozyme could be improved using this procedure,
and this trend was consistent with microscopic observations at the
level of a single giant liposome. The conditions that resulted in
good efficiencies were affected by the NaCl concentration and the
temperature of the hydration solution, implying that protein entrapment
in giant liposomes may be enhanced by associative interaction between
lipid lamellar membranes and target proteins
Percutaneous Transluminal Coronary Angioplasty for Postoperative Left Coronary Artery Stenosis Following Surgical Reconstruction of Congenital Atresia of the Left Main Coronary Artery
Murahashi Coupling Polymerization: Nickel(II)–N-Heterocyclic Carbene Complex-Catalyzed Polycondensation of Organolithium Species of (Hetero)arenes
Revisiting
Murahashi coupling, we found that it effectively allows
polymerization of lithiated (hetero)arenes by nickel(II)-catalyzed
polycondensation. Deprotonative polymerization of 2-chloro-3-substituted
thiophene with <i>n</i>-butyllithium gave head-to-tail-type
poly(3-substituted thiophene). Poly(1,4-arylene)s were obtained by
the reaction of the corresponding dibromides through lithium–bromine
exchange. A lithiated thiophene derivative obtained via deprotonative
halogen dance also underwent polymerization to afford a bromo-substituted
polythiophene
γ-Secretase Modulators and Presenilin 1 Mutants Act Differently on Presenilin/γ-Secretase Function to Cleave Aβ42 and Aβ43
Deciphering the mechanism by which the relative Aβ42(43) to total Aβ ratio is regulated is central to understanding Alzheimer disease (AD) etiology; however, the mechanisms underlying changes in the Aβ42(43) ratio caused by familial mutations and γ-secretase modulators (GSMs) are unclear. Here, we show in vitro and in living cells that presenilin (PS)/γ-secretase cleaves Aβ42 into Aβ38, and Aβ43 into Aβ40 or Aβ38. Approximately 40% of Aβ38 is derived from Aβ43. Aβ42(43) cleavage is involved in the regulation of the Aβ42(43) ratio in living cells. GSMs increase the cleavage of PS/γ-secretase-bound Aβ42 (increase kcat) and slow its dissociation from the enzyme (decrease kb), whereas PS1 mutants and inverse GSMs show the opposite effects. Therefore, we suggest a concept to describe the Aβ42(43) production process and propose how GSMs act, and we suggest that a loss of PS/γ-secretase function to cleave Aβ42(43) may initiate AD and might represent a therapeutic target