Cytotoxicity of Aβ 1-42, RAGE23-54, and An Aβ -RAGE Complex in PC-12 Cells

Title: Cytotoxicity of Aβ 1-42, RAGE23-54, and An Aβ -RAGE Complex in PC-12 Cells

Volume: 4 Issue: 5

Author(s): Shyamala Mruthinti, Nicholas Capito, Ajay Sood and Jerry J. Buccafusco

Affiliation:

Keywords: Amyloid, glycation end products, mitochondrial function, cultured cells, protein complexes

Abstract: The receptor for advanced glycation end products (RAGE) binds amyloid peptides with high affinity. Soluble RAGE-like peptides and Aβ-like peptides occur in relatively high concentrations in the circulation of individuals with Alzheimers disease. Protein complexes with epitopes for both Aβ and RAGE are also present. At physiological concentrations, forms of Aβ have different, but relatively low potencies as cytotoxicants in neural cells in culture. The purpose of this study was to determine whether a synthetic peptide complex composed of Aβ1-42 and RAGE23-54, a conserved Nterminal fragment of RAGE, exhibited increased cytotoxicity in comparison with the constituent peptides. Western analysis indicated that Aβ1-42 and RAGE23-54 remained primarily in their original low molecular weight states (4-6 kDa) during the maintenance of the individual peptides (37 ° C) in water from 1 to 4 weeks. In contrast, over the same maintenance periods the combined Aβ1-42 and RAGE23-54 peptides shifted to higher molecular weight complexes (up to 80-120 kDa). Protein complexes of similar molecular weights with epitopes for Aβ and RAGE antibodies were identified in human plasma. Incubation of differentiated PC-12 cells with 10-100 μM Aβ1-42 or with RAGE23-54 resulted in concentration-dependent decreases in cell viability. The cytotoxicity of each peptide was slightly enhanced by the progressive maintenance of Aβ1- 42 and RAGE23-54 in water over 3 weeks prior to the assay. Under the same conditions, the Aβ1-42 - RAGE23-54 complex became significantly more cytotoxic. These results suggest that the formation of soluble Aβ-RAGE complexes in Alzheimers disease could represent a mechanism for enhancing the neurotoxicity of amyloid peptides.

Cite this article as:

Mruthinti Shyamala, Capito Nicholas, Sood Ajay and Buccafusco J. Jerry, Cytotoxicity of Aβ 1-42, RAGE23-54, and An Aβ -RAGE Complex in PC-12 Cells, Current Alzheimer Research 2007; 4 (5) . https://dx.doi.org/10.2174/156720507783018325