‘Click’ assembly of glycoclusters and discovery of a trehalose analogue that retards Aβ40 aggregation and inhibits Aβ40-induced neurotoxicity

Abstract

Abstract:Osmolytes have been proposed as treatments for neurodegenerative proteinopathies including Alzheimer's disease. However, for osmolytes to reach the clinic their efficacy must be improved. In this work, copper(I)-catalyzed azide-alkyne cycloaddition chemistry was used to synthesize glycoclusters bearing six copies of trehalose, lactose, galactose or glucose, with the aim of improving the potency of these osmolytes via multivalency. A trehalose glycocluster was found to be superior to monomeric trehalose in its ability to retard the formation of amyloid-beta peptide 40 (Aβ40) fibrils and protect neurons from Aβ40-induced cell death. Keywords:Alzheimer's disease amyloid beta-peptides click chemistry glycoclusters osmolytes Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia.1 Currently, only symptomatic treatments are available and there is an urgent need for a disease-modifying drug.2 According to the modified amyloid cascade hypothesis, 3 AD is caused by small, soluble aggregates of amyloidbeta peptide (Aβ) which are highly neurotoxic. 4 It follows that one strategy to combat AD is to minimize the exposure of neurons to these aggregates and approaches to achieve this include: a) inhibiting the production of Aβ; 5,6 b) inhibiting Aβ aggregation; 7 c) promoting off-pathway aggregation that produces non-toxic Aβ aggregates; 8 and d) improving clearance of Aβ. 9,10 Recently, osmolytes have been proposed as treatments for neurodegenerative proteinopathies including AD. 11 Osmolytes are small organic molecules that protect intracellular macromolecules from denaturation caused by environmental stresses such as perturbing solutes, dehydration, desiccation, extreme temperature, and high hydrostatic pressure.12-14 There are three major categories of stabilizing osmolytes: carbohydrates; amino acids; and methylammonium/methylsulfonium compounds. 12,13 Many carbohydrate osmolytes have been found both to inhibit Aβ aggregation and to attenuate Aβ-induced neurotoxicity. Trehalose inhibits Aβ40/42 aggregation, dissociates pre-formed Aβ40/42 aggregates and decreases the toxicity of Aβ40. 15,16 Similarly, polymers carrying trehalose suppress Aβ40/42 fibril formation and reduce Aβ40/42-induced cytotoxicity.17,18 Myo-, scyllo-, and epi-inositol stabilize a nonfibrillar Aβ42 structure and attenuate Aβ42-induced neurotoxicity.19-21 Fructose inhibits fibrillogenesis of Aβ40/42 22 and attenuates Aβ42-induced neurotoxicity. 23 In many of these cases, the carbohydrate osmolytes were active at millimolar concentrations and for them to become viable treatments for AD their effectiveness must be improved. It is well established that weak interactions between proteins and carbohydrates can be amplified by constructing multivalent carbohydrate ligands and this phenomenon is known as the "cluster glycoside effect". 24,25 However, very few studies have investigated whether this phenomenon applies to carbohydrate osmolyte-Aβ interactions and then only for high MW glycopolymers. 17,18 ...

Aqueous RAFT Synthesis of Glycopolymers for Determination of Saccharide Structure and Concentration Effects on Amyloid β Aggregation

“…For the PGlcEAm35 solution, A β aggregation rate is initially reduced (Figure 3C, ○), but saturation occurs at similar intensities within 36 h. This suggests that the A β aggregation rate is influenced by the polymers PDMA, PGalEAm, and PGlcEAm35, but these polymers do not influence the final product of A β aggregation (fibrils). Fung et al 21 reported a decrease of the lag phase of A β 42 aggregation in the presence of glucose and galactose monosaccharides, whereas Rajaram et al 44 reported a concentration dependent increase in lag phase for A β 40 aggregation in the presence of glycoclusters made of six units of either glucose or galactose. We observed a minor decrease in lag phase for A β 42 aggregation in the presence of PDMA, PGalEAm, and PGlcEAm35 (Figure 3A–C).…”

Metal chelation, radical scavenging and inhibition of Aβ42 fibrillation by food constituents in relation to Alzheimer’s disease

“…The method used was based on our published protocol (Rajaram et al, 2014), with the main difference being that Aβ 42 was used instead of Aβ 40 . Briefly, low molecular weight (LMW)…”

Recent Advances in the Synthesis and Biological Activity of 8-Hydroxyquinolines

“…The connection between these units was accomplished by O -glycosidic bond or via O -methylene 1,2,3-triazole linker, as shown in Scheme 11 . Sugar derivatives of 44 and 45 were prepared according to published procedures [ 30 , 31 , 32 ]; sugar was used to enhance the bioavailability and solubility of potential drugs.…”