Metal Ions in Alzheimer’s Disease: A Key Role or Not?

Abstract

Despite tremendous research efforts in universities and pharmaceutical companies, effective drugs are still laking for the treatment of Alzheimer's disease (AD). The biochemical mechanisms of this devastating neurodegenerative disease have not yet been clearly understood. Beside a small percentage of cases with early-onset disease having a genetic origin (< 5%, familial AD), most patients develop in elderly a sporadic form due to the multiple and complex parameters of aging. Consequently, AD is spreading in all countries with a long life-expectancy. AD is characterized by deposition of senile plaques made of β-amyloid proteins (Aβ) and by hyperphosphorylation of tau proteins, which have been considered as the main drug targets up to now. However, antibodies targeting amyloid aggregates, as well as enzyme inhibitors aiming to modify the amyloid precursor protein processing, have failed to improve cognition in clinical trials. Then, to set up effective drugs, it is urgent to enlarge the panel of drug targets. Evidences of the link between AD and redox metal dysregulation have also been supported by post-mortem analyses of amyloid plaques, which contained accumulation of copper, iron, and zinc by 5.7, 2.8, and 3.1 times the levels observed in normal brains, ? Alzheimer's disease: deregulation of redox metals Cu, Fe in the brain Cu-Aβ Cu-proteins

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

“…Therapeutic chelators must take into account the necessary coordination to select suitable candidates and the possible success in clinical trials. Therefore, many attempts are made to find metal chelators as drug candidates in recent years, but few chelators have been rationally designed to create safe and effective drugs [137]. As severe deficiency of metal ions has also been observed in the AD brains and it may also contribute to AD neurodegeneration, therefore, supplement of specific Fig.…”

Protection from the Pathogenesis of Neurodegenerative Disorders, including Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Huntington’s Disease, and Parkinson’s Diseases, through the Mitigation of Reactive Oxygen Species

“…Alzheimer disease is a brain-speci ic disorder characterized by the presence of tau NFT, neural in lammation, and Aβ plaques [51][52][53]. These pathologies cause neuronal death and concomitant clinical symptoms, such as confusion, impaired cognitive function, and memory loss [54][55][56].…”

A lipid-leakage model for Alzheimer’s Disease

“…Certainly, there is substantial evidence to suggest that both Aβ and its precursor APP contain high affinity binding sites for metal such as copper, zinc and iron, with amyloid plaques seen to be highly enriched with these metals, some of which are redox-active (Barnham et al, 2003;Huang et al, 2004;Smith, Cappai & Barnham, 2007;Strozyk et al, 2009;Liu et al, 2019). And subsequent findings have led many researchers to propose a positive feedback mechanism whereby Aβ amyloidosis and metal-induced oxidative stress reinforce each other, thus contributing strongly to AD-associated neuropathology (Huang et al, 2004;Smith, Cappai & Barnham, 2007;Strozyk et al, 2009;Faller, 2009).…”

“…Furthermore, there is, as yet, no convincing evidence that therapeutic metal chelation has any substantial impact, if at all, in slowing down AD progression, leading some to question the relevance of such metal-induced oxidative stress to AD (Drew, 2017;Liu et al, 2019).…”