Active-site environment of Cu bound amyloid β and amylin peptides.

Abstract

Alzheimer's disease (AD) and Type 2 Diabetes mellitus (T2Dm), two of the most common amyloidogenic diseases. They share a common pathological symptom, i.e., the formation of amyloid deposits comprised of amyloid β and amylin peptides, respectively. Autopsy of brains of AD-affected patients shows the presence of abnormally high concentrations of Cu in the deposited amyloid β plaques, while a significantly higher level of Cu is found in the serum of patients suffering from T2Dm. These invoke that Cu might play a crucial role in the onset of both AD and T2Dm. In fact, Cu is found to bind amyloid β as well as amylin relevant to AD and T2Dm, respectively. Cu-Aβ and Cu-amylin in their reduced states can generate partially reduced oxygen species (PROS) on reaction with O2 which leads to oxidative stress in the brain and in the pancreas, respectively. However, the pathway of O2 reduction is quite different for the two complexes. Moreover, the use of various spectroscopic techniques such as absorption, EPR, and CD involving native and site-directed mutants of the peptides show that their active-site environments are also dissimilar. Here, we have discussed the different aspects of Cu-Aβ and Cu-amylin complexes including their pH-dependent coordination environments and their reactivity towards O2 which may be responsible for the oxidative stress associated with the two diseases. This depicts the significance of the Cu bound peptide complexes in the context of AD and T2Dm. Graphic abstract.