Studies On The Copper Binding Properties Of The Peptides Associated With Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterized, histopathologically, by the presence of two aberrant structures, neurofibrillary tangles (NFT) whose main composition is tau protein and senile plaques (SP) whose main composition is Aβ. It has been reported that copper (II) is concentrated in AD brain and plays an important role in the formation of AD. In the present study, employing a range of spectroscopic techniques including UV-visible absorption spectroscopy, circular dichroism (CD), NMR, fluorescence spectroscopy, matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS), and electrospray ionization mass spectrometry (ESI-MS), the copper binding properties of tau peptides and Aβpeptide have been explored fully. On the basis of the study, it is assumed that the binding of Cu2+ to tau protein may play an important role in the formation of AD. In addition, some strong data are provided for solving some controversies about the copper binding properties of Aβ.By means of UV-visible absorption spectroscopy and CD, it is shown that copper binding to R2 (VQSKCGSKDNIKHVPGGG) and R3 (VTSKCGSLGNIHHKPGGG) which derive from tau protein is highly pH dependent. In addition, all four copper binding sites of R2 and R3 are also determined, and both R2 and R3 form a type II square-planar coordination geometry with Cu2+ via these binding sites. The most important is that Cu2+ has a great influence on the conformation of R2 and R3, and the content ofαhelices in both peptides increases with the increasing amounts of Cu2+. However, for R3,αhelices are disrupted andβsheet structures form in R3 in the presence of more than 1.0 mol eq of Cu2+. Becauseαhelices andβsheet structures are responsible for the formation of paired helical filaments (PHF) whose main composition is tau protein, it is hypothesized that Cu2+ is an inducer of self-assemble of R2 and R3 and makes these two peptides form astructure like PHF. Hence it is postulated that Cu2+ plays an important role in the aggregation of R2, R3, and tau protein and copper (II) binding may be another possible involvement in AD.Some experiments have been carried out to explore the copper binding properties of Aβ(1-16) in order to provide some useful data for solving some controversies about copper binding properties of Aβ. Firstly, competition studies with glycine and L-histidine indicates copper binds to Aβ(1-16) at pH 7.8 with an affinity of Ka ~107 M-1. Secondly, Aβ(1-16) forms a type II square-planar coordination geometry with Cu2+ via OH of aromatic ring of Tyr10 andεN of imidazole ring of His6, His13, and His14, and. Finally, the binding mode between Aβ(1-16) and Cu2+ is mononuclear type 2 Cu2+.