Copper, Iron, Selenium and Lipo-Glycemic Dysmetabolism in Alzheimer’s Disease

Abstract

The aim of the present review is to discuss traditional hypotheses on the etiopathogenesis of Alzheimer’s disease (AD), as well as the role of metabolic-syndrome-related mechanisms in AD development with a special focus on advanced glycation end-products (AGEs) and their role in metal-induced neurodegeneration in AD. Persistent hyperglycemia along with oxidative stress results in increased protein glycation and formation of AGEs. The latter were shown to possess a wide spectrum of neurotoxic effects including increased Aβ generation and aggregation. In addition, AGE binding to receptor for AGE (RAGE) induces a variety of pathways contributing to neuroinflammation. The existing data also demonstrate that AGE toxicity seems to mediate the involvement of copper (Cu) and potentially other metals in AD pathogenesis. Specifically, Cu promotes AGE formation, AGE-Aβ cross-linking and up-regulation of RAGE expression. Moreover, Aβ glycation was shown to increase prooxidant effects of Cu through Fenton chemistry. Given the role of AGE and RAGE, as well as metal toxicity in AD pathogenesis, it is proposed that metal chelation and/or incretins may slow down oxidative damage. In addition, selenium (Se) compounds seem to attenuate the intracellular toxicity of the deranged tau and Aβ, as well as inhibiting AGE accumulation and metal-induced neurotoxicity.

Gene-environment interaction analysis of redox-related metals and genetic variants with plasma metabolic patterns in a general population from Spain: The Hortega Study

“…While tightly regulated levels are needed for physiological functions, overload and deficiency of these metals could lead to pathological conditions. For instance, extreme Cu and Zn levels have been associated to CVD [ 2 , 71 ], metabolic [ 149 ] and neurodegenerative diseases [ 150 , 151 ], and Se levels have been related to diabetes [ 152 ] and cardiometabolic risk [ 153 , 154 ], consistently with our data. Overall, the displayed interconnections of enriched pathways attributed to the genes interacting with metals is consistent with the hypothesis that metals can directly and indirectly influence redox-related pathways in common for human chronic diseases.…”

“…Findings from the integrative biological pathway analysis are consistent with accumulated evidence supporting that non-essential metal exposures could play a role in the pathogenesis of several conditions, including CVD for Sb [ 5 , 49 ], As [ 71 ] and Cd [ 71 ], cancer and renal dysfunction for Cd [ 67 , 141 , 142 ] and As [ 67 , [143] , [144] , [145] ] and neurological disorders for As [ 146 , 147 ] and Cd [ 148 ]. However, the evidence assessing the potential health-effects of essential metals is less clear [ 2 , 4 , 71 , [149] , [150] , [151] ]. While tightly regulated levels are needed for physiological functions, overload and deficiency of these metals could lead to pathological conditions.…”

Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis?

“…The pathological mechanism of AD is too complex to explain it merely with Aβ and tau accumulation. Scientists have found that many pathological processes, for instance, neural inflammation ( Leng and Edison, 2021 ), oxidative stress ( Song et al, 2021 ) and metal dysregulation ( Wang et al, 2020 ; Aaseth et al, 2021 ), involved in Aβ deposition and tau hyperphosphorylation, driving the insidious progression before AD diagnosis. Currently, the involvement of iron in the early pathology of AD has been well accepted since the discovery of the link between dysregulation of brain iron homeostasis and AD pathogenesis in 1953 ( Goodman, 1953 ).…”

“…Growing evidence have proved that Aβ triggers the chain events downstream in the pathological course of AD, including tau pathology. However, other processes such as neural inflammation ( Leng and Edison, 2021 ), oxidative stress ( Song et al, 2021 ), apoptosis ( Sharma et al, 2021 ), autophagy ( Zhang et al, 2021 ) and metal dysregulation ( Wang et al, 2020 ; Aaseth et al, 2021 ) are also found in AD pathology. Some of these processes are even involved in the deposition of Aβ.…”

Cerebral Iron Deposition in Neurodegeneration

“…•− ), but may not necessarily produce more ROS in aging [15] as damaged mitochondria are removed by autophagy [16]. Iron and ROS generation are involved in ferroptosis, a recently described form of cell death which is defined as iron-dependent regulated necrosis that is caused by massive lipid peroxidation-mediated membrane damage [17,18].…”