Biometal Dyshomeostasis and Toxic Metal Accumulations in the Development of Alzheimer’s Disease

Abstract

Biometal dyshomeostasis and toxic metal accumulation are common features in many neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease, and Huntington’s disease. The neurotoxic effects of metal imbalance are generally associated with reduced enzymatic activities, elevated protein aggregation and oxidative stress in the central nervous system, in which a cascade of events lead to cell death and neurodegeneration. Although the links between biometal imbalance and neurodegenerative disorders remain elusive, a major class of endogenous proteins involved in metal transport has been receiving increasing attention over recent decades. The abnormal expression of these proteins has been linked to biometal imbalance and to the pathogenesis of AD. Here, we present a brief overview of the physiological roles of biometals including iron, zinc, copper, manganese, magnesium and calcium, and provide a detailed description of their transporters and their synergistic involvement in the development of AD. In addition, we also review the published data relating to neurotoxic metals in AD, including aluminum, lead, cadmium, and mercury.

A Unique GSK-3β inhibitor B10 Has a Direct Effect on Aβ, Targets Tau and Metal Dyshomeostasis, and Promotes Neuronal Neurite Outgrowth

“…Metal dyshomeostasis plays important roles in AD pathogenesis by preceding or inducing NFTs, senile plaques, and reactive oxygen species (ROS) [14][15][16][17]. Cu 2+ , Zn 2+ , and Fe 2+ are known to excessively exist in the senile plaques [17,40].…”

“…Metal dyshomeostasis plays important roles in AD pathogenesis by preceding or inducing NFTs, senile plaques, and reactive oxygen species (ROS) [14][15][16][17]. Cu 2+ , Zn 2+ , and Fe 2+ are known to excessively exist in the senile plaques [17,40]. As one of the main cationic elements in plaque formation, copper ion binds to Aβ, promoting its accumulation and inducing ROS generation and oxidative stress [41,42].…”

“…These drugs provide only limited efficiency and curable drugs remain lacking. Several hypotheses are put forth to explain the causes of AD, mainly including the amyloid cascade hypothesis [6,7], tau pathology [8,9], cholinergic hypothesis [10,11], inflammatory [12,13], metal ion dyshomeostasis [14][15][16][17], and oxidative stress [18,19]; however, the exact AD etiology is still unclear. Since AD is a complicated disease with multifaceted pathogenesis, the one-drug-one-target strategy is not very effective, and therefore, the multitarget-directed ligands that simultaneously interfere with the multiple processes of AD progression are more hopeful [20][21][22][23].…”

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

“…Environmental toxicants have been extensively linked to neurodegenerative disorders [24,25]. Homeostatic dysregulation of metals in brain cells and tissues or the accumulation of toxic metals have been linked to various neurodegenerative diseases, including AD [26,27]. Lead (Pb) is known to be neurotoxic and perturbs Aβ generation and clearance [28], and Pb exposure has been implicated in AD [29], but case-control studies have not nailed down a clear link between tissue Pb accumulation and AD [30].…”

<p>Treatment Of Magnesium-L-Threonate Elevates The Magnesium Level In The Cerebrospinal Fluid And Attenuates Motor Deficits And Dopamine Neuron Loss In A Mouse Model Of Parkinson’s disease</p>

“…High concentration of aluminum and low concentration of Mg and calcium in the water consumed by Chamorro natives have been reported for the high incidence of PD in Guam. 5 To further investigate the pathogenesis of PDC, a study was designed to limit the intake of Mg and calcium in rats over two generations. The intention of the study was to simulate the conditions for humans on Guam.…”