Second Sphere Interactions in Amyloidogenic Diseases

Abstract

Amyloids are protein aggregates bearing a highly ordered cross β structural motif, which may be functional but are mostly pathogenic. Their formation, deposition in tissues and consequent organ dysfunction is the central event in amyloidogenic diseases. Such protein aggregation may be brought about by conformational changes, and much attention has been directed toward factors like metal binding, post-translational modifications, mutations of protein etc., which eventually affect the reactivity and cytotoxicity of the associated proteins. Over the past decade, a global effort from different groups working on these misfolded/unfolded proteins/peptides has revealed that the amino acid residues in the second coordination sphere of the active sites of amyloidogenic proteins/peptides cause changes in H-bonding pattern or protein–protein interactions, which dramatically alter the structure and reactivity of these proteins/peptides. These second sphere effects not only determine the binding of transition metals and cofactors, which define the pathology of some of these diseases, but also change the mechanism of redox reactions catalyzed by these proteins/peptides and form the basis of oxidative damage associated with these amyloidogenic diseases. The present review seeks to discuss such second sphere modifications and their ramifications in the etiopathology of some representative amyloidogenic diseases like Alzheimer’s disease (AD), type 2 diabetes mellitus (T2Dm), Parkinson’s disease (PD), Huntington’s disease (HD), and prion diseases.

Spin state dependent peroxidase activity of heme bound amyloid β peptides relevant to Alzheimer's disease

“…Alzheimer's disease (AD) is a neurodegenerative disorder, which is clinically characterized by progressive loss of brain functions. [1][2][3][4] It is the most common form of senile dementia with symptoms like confusion, rapid mood swings, apraxia and long-term memory loss that eventually culminates in death. [4][5][6] Although the exact cause of AD has remained elusive to date, research over the years into the etiopathology of this disease has resulted in the proposal of some important hypotheses, among which the "amyloid cascade hypothesis" is most widely known.…”

“…4,10 Apart from Ab, transition metals like Cu and Zn are also found within the senile plaques, both of which have been reported to strongly bind the Ab peptide. 4,[9][10][11][12] Cu, as a redox active metal, has been proposed to cause oxidative stress that can lead to neuronal cell damage, nucleic acid adduct formation, neurotransmitter oxidation, etc. [13][14][15][16][17][18] Zn, on the other hand, has signicant contribution to Ab deposition.…”

“…This small peptide is generated from a transmembrane protein called the amyloid precursor protein (APP) by the action of secretase enzymes. 4,6,10 The Aβ peptides containing 40 and 42 amino acids i.e. , Aβ(1-40) and Aβ(1-42) respectively, are the most abundant in the AD brain.…”

“…The binding of heme to Aβ has been proposed to result in the depletion of regulatory heme, which may explain the observation of heme deficiency symptoms in AD. 4,27,31,39 Recent Raman imaging of AD brain tissue has revealed that, heme present in Aβ plaques in the brain tissue resembles a six coordinated low-spin species that may possibly be a bis-His low-spin heme–Aβ species. 40…”

“…[1][2][3][4] It is the most common form of senile dementia with symptoms like confusion, rapid mood swings, apraxia and long-term memory loss that eventually culminates in death. [4][5][6] Although the exact cause of AD has remained elusive to date, research over the years into the etiopathology of this disease has resulted in the proposal of some important hypotheses, among which the "amyloid cascade hypothesis" is most widely known. 4,7,8 According to this hypothesis, the main histopathological criterion of AD is the extracellular deposition of amyloid brils made up of the amyloid b (Ab) peptide to form structures known as senile plaques, 3,4,[7][8][9] which are neurotoxic.…”