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

Abstract

Background: The homeostasis of metal ions, such as iron, copper, zinc and calcium, in the brain is crucial for maintaining normal physiological functions. Studies have shown that imbalance of these metal ions in the brain is closely related to the onset and progression of Alzheimer's disease (AD), the most common neurodegenerative disorder in the elderly.

Main body: Erroneous deposition/distribution of the metal ions in different brain regions induces oxidative stress. The metal ions imbalance and oxidative stress together or independently promote amyloid-β (Aβ) overproduction by activating β- or γ-secretases and inhibiting α-secretase, it also causes tau hyperphosphorylation by activating protein kinases, such as glycogen synthase kinase-3β (GSK-3β), cyclin-dependent protein kinase-5 (CDK5), mitogen-activated protein kinases (MAPKs), etc., and inhibiting protein phosphatase 2A (PP2A). The metal ions imbalances can also directly or indirectly disrupt organelles, causing endoplasmic reticulum (ER) stress; mitochondrial and autophagic dysfunctions, which can cause or aggravate Aβ and tau aggregation/accumulation, and impair synaptic functions. Even worse, the metal ions imbalance-induced alterations can reversely exacerbate metal ions misdistribution and deposition. The vicious cycles between metal ions imbalances and Aβ/tau abnormalities will eventually lead to a chronic neurodegeneration and cognitive deficits, such as seen in AD patients.

Conclusion: The metal ions imbalance induces Aβ and tau pathologies by directly or indirectly affecting multiple cellular/subcellular pathways, and the disrupted homeostasis can reversely aggravate the abnormalities of metal ions transportation/deposition. Therefore, adjusting metal balance by supplementing or chelating the metal ions may be potential in ameliorating AD pathologies, which provides new research directions for AD treatment.

Keywords: Alzheimer’s disease; Amyloid-β; Autophagy; Metal ions; Oxidative stress; Synapses; Tau.

Fig. 1

Metal ions imbalance in Alzheimer-like neurodegeneration and cognitive deficits. The metal ions (Fe, Cu, Zn and Ca) imbalance induces oxidative stress demonstrated by the reduced level/activity of GSH, SOD1 and ATOX1 and an increased level of ROS. Oxidative stress can induce tau hyperphosphorylation by activating protein kinases (such as GSK-3β, CDK5, MAPK, etc.) and/or inhibiting PP2A; it can also promote Aβ overproduction by activating β- and γ-secretases and/or inhibiting α-secretase. Together with the imbalanced metal ions and oxidative stress, or independently, the hyperphosphorylated tau (p-tau) and overproduced Aβ could induce ER stress, mitochondrial dysfunction, and autophagic impairments, leading to p-tau and Aβ aggregation and accumulation. Again, together with p-tau/Aβ accumulation, autophagic/mitochondrial deficits, ER stress and oxidative stress, or independently, the imbalanced metal ions can induce synapse damages, which causes synaptic dysfunction, neurodegeneration, and eventually learning and memory deficits. As indicated in the figure by the double-sided arrows, many of these pathological processes occur in a bi-directional way and thus form a vicious cycle during the age-dependent chronic neurodegeneration, such as seen in AD