Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture

Alzheimer's disease (AD) is pathologically characterised by the age-dependent deposition of β-amyloid (Aβ) in senile plaques, intraneuronal accumulation of tau as neurofibrillary tangles, synaptic dysfunction and neuronal death. Neuroinflammation, typified by the accumulation of activated microglia and reactive astrocytes, is believed to modulate the development and/or progression of AD. We have used primary rat neuronal, astrocytic and mixed cortical cultures to investigate the contribution of astrocyte-mediated inflammatory responses during Aβ-induced neuronal loss. We report that the presence of small numbers of astrocytes exacerbate Aβ-induced neuronal death, caspase-3 activation and the production of caspase-3-cleaved tau. Furthermore, we show that astrocytes are essential for the Aβ-induced tau phosphorylation observed in primary neurons. The release of soluble inflammatory factor(s) from astrocytes accompanies these events, and inhibition of astrocyte activation with the anti-inflammatory agent, minocycline, reduces astrocytic inflammatory responses and the associated neuronal loss. Aβ-induced increases in caspase-3 activation and the production of caspase-3-truncated tau species in neurons were reduced when the astrocytic response was attenuated with minocycline. Taken together, these results show that astrocytes are important mediators of the neurotoxic events downstream of elevated Aβ in models of AD, and suggest that mechanisms underlying pro-inflammatory cytokine release might be an important target for therapy

The direct formation of glycosyl thiols from reducing sugars allows one-pot protein glycoconjugation

(Figure Presented) Sweet and easy: A one-pot method consisting of direct thionation (1) followed by thiol-mediated chemoselective ligation (2) can be used for site-selective protein glycosylation. This procedure, which uses the Lawesson reagent, has been shown to be fully compatible with unprotected sugars, the products of which can be directly used in a selenenylsulfide protein glycosylation strategy. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA

The direct formation of glycosyl thiols from reducing sugars allows one-pot protein glycoconjugation.

(Figure Presented) Sweet and easy: A one-pot method consisting of direct thionation (1) followed by thiol-mediated chemoselective ligation (2) can be used for site-selective protein glycosylation. This procedure, which uses the Lawesson reagent, has been shown to be fully compatible with unprotected sugars, the products of which can be directly used in a selenenylsulfide protein glycosylation strategy. © 2006 Wiley-VCH Verlag GmbH and Co. KGaA

Glycoprotein synthesis: an update.

A review that provides an update on an earlier review on the synthesis of glycoproteins is presented. The review focuses on highlighting key developments in the area from 2002 and provide essential information about the process. It includes specific areas of potential applications of the synthesis process to provide a detailed update. It reveals that carbohydrates continue to play a key role in the synthesis of glycoproteins. Carbohydrates are increasingly being used in synthesizing such proteins, as they are able to modify their other physiochemical properties. The review also reveals that significant developments in glycopeptide or glycoprotein synthesis are increasing the number of potential applications for such proteins. A number of biomedical researchers are developing new drug products, adopting the process of synthesizing glycoproteins

The building blocks of cellulose: the intrinsic conformational structures of cellobiose, its epimer, lactose, and their singly hydrated complexes.

A combination of vibrational spectroscopy conducted under molecular beam conditions and quantum chemical calculation has established the intrinsic three-dimensional structures of the cellulose disaccharide and, focusing on the critical beta1,4-linkage at the nonreducing end of the growing cellulose polymer, its C-4' epimer. Left to their own devices they both adopt a cis (anti-phi/syn-psi) glycosidic configuration, supported in the epimer by strong, cooperative inter-ring hydrogen bonding. In the cellulose disaccharide, however, where the OH-4'(Glc) group is equatorial, the cooperativity is reduced and the corresponding inter-ring hydrogen bonding is relatively weak. The cis conformational preference is still retained in their singly hydrated complexes. In the cellulose disaccharide insertion of the water molecule at the favored binding site between OH-4' and the neighboring hydroxyl group OH-6' promotes a structural reorganization to create a configuration that parallels that of its unhydrated epimer and greatly strengthens the inter-ring hydrogen bonding. In the C-4' epimer, the axial orientation of OH-4' blocks this binding site and the bound water molecule simply adds on at the end of the (OH-O)(n) chain, which has a negligible effect on the (already strong) inter-ring bonding. The implications of these results are discussed with respect to the structure and insolubility of native cellulose polymers

Conformational change and selectivity in explicitly hydrated carbohydrates

The combination of vibrational spectroscopy, conducted in a supersonic jet expansion, with computation through molecular mechanics, density functional theory (DFT) and ab initio calculation, has provided a new approach to the conformational and structural assignment of carbohydrates and their molecular complexes. This article reviews the new insights it has provided on the regioselectivity and conformational choice in singly and multiply hydrated monosaccharides. It reveals a systematic pattern of conformational preference and binding site selectivity, driven by the provision of optimal, co-operative hydrogen-bonded networks in the hydrated sugars. Water binding is invariably 'focused' around the hydroxymethyl group (when present); the bound water molecules (on multiply hydrated mannose) are located exclusively on its hydrophilic face while the hydrophobic face remains 'dry'; and there is a correlation between the locale of the preferred binding sites and those involved in protein-carbohydrate molecular recognition. © 2009 Elsevier Ltd. All rights reserved

Conformational change and selectivity in explicitly hydrated carbohydrates

The combination of vibrational spectroscopy, conducted in a supersonic jet expansion, with computation through molecular mechanics, density functional theory (DFT) and ab initio calculation, has provided a new approach to the conformational and structural assignment of carbohydrates and their molecular complexes. This article reviews the new insights it has provided on the regioselectivity and conformational choice in singly and multiply hydrated monosaccharides. It reveals a systematic pattern of conformational preference and binding site selectivity, driven by the provision of optimal, co-operative hydrogen-bonded networks in the hydrated sugars. Water binding is invariably 'focused' around the hydroxymethyl group (when present); the bound water molecules (on multiply hydrated mannose) are located exclusively on its hydrophilic face while the hydrophobic face remains 'dry'; and there is a correlation between the locale of the preferred binding sites and those involved in protein-carbohydrate molecular recognition. © 2009 Elsevier Ltd. All rights reserved