Modulation of amyloid beta peptide(1-42) cytotoxicity and aggregation in vitro by glucose and chondroitin sulfate.
One mechanism leading to neurodegeneration during Alzheimer's disease (AD) is amyloid beta peptide (Abeta)-induced neurotoxicity. Among the factors proposed to potentiate Abeta toxicity is its covalent modification through carbohydrate-derived advanced glycation endproducts (AGEs). Other experimental evidence, though, indicates that certain polymeric carbohydrates like the glycosaminoglycan (GAG) chains found in proteoglycan molecules attenuate the neurotoxic effect of Abeta in primary neuronal cultures. Pretreatment of the 42-residue Abeta fragment (Abeta1-42) with the ubiquitous brain carbohydrates, glucose, fructose, and the GAG chondroitin sulfate B (CSB) inhibits Abeta1-42-induced apoptosis and reduces the peptide neurotoxicity on neuroblastoma cells, a cytoprotective effect that is partially reverted by AGE inhibitors such as pyridoxamine and L-carnosine. Thioflavin T fluorescence measurements indicate that at concentrations close to physiological, only CSB promotes the formation of Abeta amyloid fibril structure. Atomic force microscopy imaging and Western blot analysis suggest that glucose favours the formation of globular oligomeric structures derived from aggregated species. Our data suggest that at short times carbohydrates reduce Abeta1-42 toxicity through different mechanisms both dependent and independent of AGE formation.
Fernàndez-Busquets
X
X
Nanobioengineering Group, Institute for Bioengineering of Catalonia, Barcelona, Spain. xfernandez_busquets@ub.edu
Ponce
J
J
Bravo
R
R
Arimon
M
M
Martiáñez
T
T
Gella
A
A
Cladera
J
J
Durany
N
N
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002809:Chondroitin Sulfates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*
D016229:Amyloid beta-Peptides; D017127:Glycation End Products, Advanced; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D002809:Chondroitin Sulfates; D005947:Glucose