Meanwhile back at the ranch ( pbt2) ... the world interest in metals and AD link is continuing to gain traction. Some articles below:
Copper and Zinc Dysregulation in Alzheimer's Disease.
Review articleSensi SL, et al. Trends Pharmacol Sci. 2018.
Abstract
Alzheimer's disease (AD) is one of the most common forms of dementia. Despite a wealth of knowledge on the molecular mechanisms involved in AD, current treatments have mainly focused on targeting amyloid β (Aβ) production, but have failed to show significant effects and efficacy. Therefore, a critical reconsideration of the multifactorial nature of the disease is needed. AD is a complex multifactorial disorder in which, along with Aβ and tau, the convergence of polygenic, epigenetic, environmental, vascular, and metabolic factors increases the global susceptibility to the disease and shapes its course. One of the cofactors converging on AD is the dysregulation of brain metals. In this review, we focus on the role of AD-related neurodegeneration and cognitive decline triggered by the imbalance of two endogenous metals: copper and zinc.
Copyright © 2018 Elsevier Ltd. All rights reserved.
A Mathematical Model for Amyloid- Aggregation in the Presence of Metal Ions: A Timescale Analysis for the Progress of Alzheimer Disease.
Asili E, et al. Bull Math Biol. 2019.
Abstract
The aggregation of amyloid- (A) proteins through their self-assembly into oligomers, fibrils, or senile plaques is advocated as a key process of Alzheimer's disease. Recent studies have revealed that metal ions play an essential role in modulating the aggregation rate of amyloid- (A) into senile plaques because of high binding affinity between A proteins and metal ions. In this paper, we proposed a mathematical model as a set of coupled kinetic equations that models the self-assembly of amyloid- (A) proteins in the presence of metal ions. The numerical simulations capture four timescales in the A dynamics associated with three important events which include the formation of the amyloid-metal complex, the homogeneous aggregation of the amyloid-metal complexes, and the non-homogeneous aggregation of the amyloid-metal complexes. The method of singular perturbation is used to identify these timescales in the framework of slow-fast systems.
Huat TJ, et al. J Mol Biol. 2019.
Abstract
As the median age of the population increases, the number of individuals with Alzheimer's disease (AD) and the associated socio-economic burden are predicted to worsen. While aging and inherent genetic predisposition play major roles in the onset of AD, lifestyle, physical fitness, medical condition, and social environment have emerged as relevant disease modifiers. These environmental risk factors can play a key role in accelerating or decelerating disease onset and progression. Among known environmental risk factors, chronic exposure to various metals has become more common among the public as the aggressive pace of anthropogenic activities releases excess amount of metals into the environment. As a result, we are exposed not only to essential metals, such as iron, copper, zinc and manganese, but also to toxic metals including lead, aluminum, and cadmium, which perturb metal homeostasis at the cellular and organismal levels. Herein, we review how these metals affect brain physiology and immunity, as well as their roles in the accumulation of toxic AD proteinaceous species (i.e., β-amyloid and tau). We also discuss studies that validate the disruption of immune-related pathways as an important mechanism of toxicity by which metals can contribute to AD. Our goal is to increase the awareness of metals as players in the onset and progression of AD.
Copyright © 2019 Elsevier Ltd. All rights reserved.
ArticleIron Exposure and the Cellular Mechanisms Linkedto Neuron Degeneration in Adult Mice
Lin-Bo Li, Rui Chai, Shuai Zhang, Shuang-Feng Xu, Yan-Hui Zhang, Hai-Long Li,Yong-Gang Fan and Chuang Guo *College of Life and Health Sciences, Northeastern University, Shenyang 110819, China;
[email protected] (L.-B.L.);
[email protected] (R.C.);
[email protected] (S.Z.);
[email protected] (S.-F.X.);
[email protected] (Y.-H.Z.);
[email protected] (H.-L.L.);
[email protected] (Y.-G.F.)* Correspondence:
[email protected]: 6 December 2018;
Accepted: 19 February 2019; Published: 24 February 2019
Abstract: Although the causal relationship between Alzheimer’s disease (AD) and iron overloadremains unclear, iron dyshomeostasis or improper transport mechanisms are speculated to lead tothe accumulation of this neurotoxic metal in the hippocampal formation and other cerebral areasrelated to neurodegenerative diseases, resulting in the formation of reactive oxygen species (ROS)and, ultimately, cell death. In this study, exposure to high dietary iron (HDI) revealed no significantdifference in the number of iron-positive cells and iron content in the cortex and hippocampalregion between wild-type (WT) and APP/PS1 mice; however, compared with the control mice, theHDI-treated mice exhibited upregulated divalent metal transporter 1 (DMT1) and ferroportin (Fpn)expression, and downregulated transferrin receptor (TFR) expression. Importantly, we confirmedthat there were significantly fewer NeuN-positive neurons in both APP/PS1 and WT mice givenHDI, than in the respective controls. Moreover, this iron-induced neuron loss may involve increasedROS and oxidative mitochondria dysfunction, decreased DNA repair, and exacerbated apoptosisand autophagy. Although HDI administration might trigger protective antioxidant, anti-apoptosis,and autophagy signaling, especially in pathological conditions, these data clearly indicate that chroniciron exposure results in neuronal loss due to apoptosis, autophagy, and ferroptosis, hence increasingthe risk for developing AD.
