Effect of Free Amino Acids on the Abnormal Accumulation of Amyloid-β Peptides

A major hallmark of Alzheimer's disease is the senile plaques in cerebral cortex and hippocampus, mainly composed of the abnormal accumulation of amyloid-beta (A beta) peptides. It was suggested that metal ions (such as copper ions) would be a possible key mediating factor for the formation of amyloid deposits by binding to A beta peptides and triggering the involved aggregation process. Some previous studies have uncovered that the concentration levels of free amino acids (aa) in the brain of AD patients are different from that of normal controls. So we investigated the interactions between copper ions and A beta peptides in the presence of free amino acids. The effects of sixteen amino acids on the copper-A beta complexes were examined by electrospray-ionization mass spectrometry (ESI-MS). Firstly, the mixture solution of A beta(10-21) peptide (10 mu mol/L) and Cu(Gly)(2) (40 mu mol/L) was incubated for 1 h at 37 degrees C in 10 mmol/L ammonium acetate buffer (pH=6.5). Then stock solution of each amino acid was added yielding A beta/Cu2+/aa mixture solution at the final concentration of 1 : 4 : x (x = 0, 1, 2, 3, 4, 5, 10) for 200 mu L total volume. After 1 h incubation, the samples were analyzed by ESI-MS. Different effects of these amino acids have been observed by comparing the mass spectrum of A beta/Cu2+/aa mixture solution with the spectrum of A beta/Cu2+ mixture solution. Because of their side chain polarity and stronger coordination ability, Asp, Glu, Leu, Tyr, Thr and His can obviously inhibit the combination between copper ions and A beta peptide at relative low concentrations, and Gln, Asn, Met, Ser and Cys can also inhibit the combination at moderate concentrations. However, Ala, Phe, Ile, Val and Lys can not inhibit at any concentration, and one of them, Lys, can even accelerate their combination. We infer that these amino acids which can inhibit the binding between A beta peptides and copper ions may have relationships with the formation of the senile plaques and take into consideration that free amino acids may be a new kind of microenvironment factor related with the abnormal accumulation of A beta peptides.National Natural Science Foundation of China [40976050]; National Public Benefit (Ocean) Research Foundation of China [201105013]; Grand Research Foundation of Fujian Province [2011YZ0001-1