The Role of Heme and Copper in Alzheimer’s Disease and Type 2 Diabetes Mellitus

Abstract

Beyond the well-explored proposition of protein aggregation or amyloidosis as the central event in amyloidogenic diseases like Alzheimer’s Disease (AD), and Type 2 Diabetes Mellitus (T2Dm); there are alternative hypotheses, now becoming increasingly evident, which suggest that the small biomolecules like redox noninnocent metals (Fe, Cu, Zn, etc.) and cofactors (Heme) have a definite influence in the onset and extent of such degenerative maladies. Dyshomeostasis of these components remains as one of the common features in both AD and T2Dm etiology. Recent advances in this course reveal that the metal/cofactor-peptide interactions and covalent binding can alarmingly enhance and modify the toxic reactivities, oxidize vital biomolecules, significantly contribute to the oxidative stress leading to cell apoptosis, and may precede the amyloid fibrils formation by altering their native folds. This perspective highlights this aspect of amyloidogenic pathology which revolves around the impact of the metals and cofactors in the pathogenic courses of AD and T2Dm including the active site environments, altered reactivities, and the probable mechanisms involving some highly reactive intermediates as well. It also discusses some in vitro metal chelation or heme sequestration strategies which might serve as a possible remedy. These findings might open up a new paradigm in our conventional understanding of amyloidogenic diseases. Moreover, the interaction of the active sites with small molecules elucidates potential biochemical reactivities that can inspire designing of drug candidates for such pathologies.

Addressing the gaps in homeostatic mechanisms of copper and copper dithiocarbamate complexes in cancer therapy: a shift from classical platinum-drug mechanisms

“…Copper( ii ) with and without Aβ may both be reduced to copper( i ) in the cellular environment that contains reducing agents (such as ascorbate and glutathione), as illustrated in copper( i )-Aβ may interact with O 2 to create ROS, such as O 2− , H 2 O 2 , and OH, which can oxidatively modify Aβ and alter its aggregation. 141–143 The copper binding sites and binding modes of monomeric Aβ peptides are flexible, and they alter dynamically with pH (Fig. 6 top (a) and (b)) and oxidation state as well as the metal centres’ responsiveness to ligand replacement and redox catalysis 136 (fig below).…”

Redox changes and cellular senescence in Alzheimer's disease

“…Patients treated with the drug demonstrated improved executive function components on tests as well as a significantly reduced Aβ42 concentration in their cerebrospinal fluids (CSF) [ 129 ]. However, metal chelation therapies can come with side effects [ 130 ], resulting from the sequestration of healthy functional metal ions and redistribution of other metal ions [ 131 ], and hence these therapies are no longer being clinically pursued [ 132 ].…”

Unveiling the Effects of Copper Ions in the Aggregation of Amyloidogenic Proteins

“…Traditionally, AD and T2DM have been considered as two separate disorders. Nevertheless, mounting epidemiological, observational, and fundamental molecular research evidence has connected T2DM to an increased risk of AD and vice versa [ 122 ]. Copper appears to play a leading role in both pathologies.…”