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Metal Ion Effects on a and Tau Aggregation

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Metal Ion Effects on a and Tau Aggregation International Journal of Molecular Sciences Review Metal Ion Effects on Aβ and Tau Aggregation Anne Claire Kim 1,2, Sungsu Lim 2 and Yun Kyung Kim 2,* 1 Department of Neuroscience, Wellesley College, Wellesley, MA 02481, USA; [email protected] 2 Brain Science Institute, Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-2-958-5072 Received: 30 November 2017; Accepted: 28 December 2017; Published: 2 January 2018 Abstract: Amyloid and tau aggregation are implicated in manifold neurodegenerative diseases and serve as two signature pathological hallmarks in Alzheimer’s disease (AD). Though aging is considered as a prominent risk factor for AD pathogenesis, substantial evidence suggests that an imbalance of essential biometal ions in the body and exposure to certain metal ions in the environment can potentially induce alterations to AD pathology. Despite their physiological importance in various intracellular processes, biometal ions, when present in excessive or deficient amounts, can serve as a mediating factor for neurotoxicity. Recent studies have also demonstrated the contribution of metal ions found in the environment on mediating AD pathogenesis. In this regard, the neuropathological features associated with biometal ion dyshomeostasis and environmental metal ion exposure have prompted widespread interest by multiple research groups. In this review, we discuss and elaborate on findings from previous studies detailing the possible role of both endogenous and exogenous metal ions specifically on amyloid and tau pathology in AD. Keywords: metal; tau; β-amyloid 1. Introduction Aided by the advances in medical technologies, the elderly population is increasing rapidly, and the world is now facing the ‘ageing era’, which comes with social issues like dementia. Alzheimer’s disease (AD) is the leading cause of dementia, affecting one-third of all people age 85 [1]. Ageing is recognized as the most important risk factor for AD, but a combination of genetic, environmental, and lifestyle factors also contribute to the onset of AD [2]. To reduce the risk of developing AD or help to treat it, substantial efforts have been made to identify the molecular causes of AD. Recently, accumulating evidence has suggested that metal dyshomeostasis in the brain is closely linked with age-related neurodegenerative disorders including AD. Metal ions are essential for life, playing important roles in the human body. In nature, nearly half of all proteins are metal-binding proteins called metalloproteins [3]. Protein-bound metal cations such as copper (Cu2+, Cu+), iron (Fe3+, Fe2+), magnesium (Mg2+), manganese (Mn2+), calcium (Ca2+), and zinc (Zn2+) are key elements for maintaining cell structure, regulating gene expression, mediating cell signaling as a second messenger, and catalyzing enzyme activities [4]. The brain, in particular, requires high levels of free metal ions in synaptic clefts as a modulator of synaptic transmission. Accordingly, metal dyshomeostasis directly causes neuronal dysfunction [5], leading to neuronal cell death [6]. Clinical studies have shown elevated levels of Cu, Fe, and Zn ions in post-mortem brain tissues of AD patients [7]. In addition to biometal dyshomeostsis, exposure to environmental heavy metals such as mercury (Hg2+), cadmium (Cd2+), lead (Pb2+), aluminum (Al2+), and lithium (Li+) is neuro-toxic [8], leading to the activation of AD pathology (Figure1). Int. J. Mol. Sci. 2018, 19, 128; doi:10.3390/ijms19010128 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2018, 19, 128 2 of 15 AD pathology involves a wide variety of neurotoxic pathways such as abnormal protein Int. J. Mol. Sci. 2018, 19, 128 2 of 15 aggregation, mitochondria dysfunction, reduced synthesis of neurotransmitters, inflammation, and oxidative stress stress in the brain. Among them, accumulation of of amyloid ββ (A(Aββ)) and and tau aggregates is considered the most dominant etiologic paradigmparadigm of Alzheimer’s pathology [[9].9]. A β isis a a 39 39 to to 43 43 amino amino acid long long peptide peptide generated generated through through abnormal abnormal prot proteolysiseolysis of ofthe the amyloid amyloid precursor precursor protein protein (APP) (APP) by βby- andβ- and γ-secretases.γ-secretases. Once Once the the Aβ A βpeptidepeptide is issecreted, secreted, it it spontane spontaneouslyously transforms transforms into into neurotoxic oligomers and and fibrils, fibrils, which which damage neuronal neuronal cells cells [ [10]10] (Figure 11a).a). InIn contrast,contrast, tautau isis anan abundantabundant protein in the brain, supporting ne neuronaluronal structures and functions [ 11].11]. Under Under pathological pathological conditions, conditions, tautau is abnormallyabnormally hyper-phosphorylated,hyper-phosphorylated, and and the hyper-phosphorylatedhyper-phosphorylated tau tau a aggregatesggregates into fibrilsfibrils called neurofibrillary neurofibrillary tangles tangles (NFTs) (NFTs) (Figure 11b).b). AbnormalAbnormal tau tanglestangles areare accumulatedaccumulated in neurons,neurons, causing neuronal toxicity and neurodegeneration [12]. [12]. Metal Metal dysh dyshomeostasisomeostasis has has been been suggested as a strong neurotoxic candidate that induces changes in A β and tau aggregation. Here, Here, we we will review the pathological roles roles of of metal metal ions ions in in the the alte alterationration of of amyloidogenesis amyloidogenesis and and tau tau pathology. pathology. Figure 1. Metal ions effect on amyloidamyloid β (A(Aβ) andand tautau aggregation.aggregation. (a) AmyloidogenesisAmyloidogenesis [13]. [13]. Under normal conditions, conditions, A Aβ βis rarelyis rarely produced produced in the in brain, the brain, since sinceamyloid amyloid precursor precursor protein protein(APP) is (APP) cleaved is bycleaved α- and by γ-secretase.α- and γ-secretase. Under pathological Under pathological conditions, conditions, APP is cleaved APP with is cleaved β- and with γ-secretase,β- and γ generating-secretase, neurotoxicgenerating A neurotoxicβ peptide. A Onceβ peptide. the A Onceβ peptide the A isβ peptidegenerated is generatedand secreted and into secreted the extracellular into the extracellular space, it spontaneouslyspace, it spontaneously transforms transforms into fibrils into called fibrils amyloid called plaques. amyloid Zn plaques.2+, Cu2+, Fe Zn3+2+, Mn, Cu2+,2+ Pb, Fe2+, 3+Cd,2+ Mn, Hg2+2+,, Pb and2+, AlCd3+2+ induce, Hg2+ ,amyloidogenic and Al3+ induce pathways amyloidogenic and Aβ aggregation pathways and (red A βarrow).aggregation In contrast, (red arrow).Mg2+, Fe In2+, contrast,and Li2+ reduceMg2+, Fethe2+ ,formation and Li2+ reduce of Aβ the(blue formation arrow); of(b A) Tauβ (blue pathology. arrow); (Inb) Taua nonpathological pathology. In a condition, nonpathological tau is constantlycondition, tauphosphorylated is constantly and phosphorylated dephosphorylated and dephosphorylated for the maintenance for the ofmaintenance neuronal structure of neuronal and function.structure Under and function. pathological Under condition, pathological tau is condition, highly phosphorylated tau is highly phosphorylated by diverse kinases bydiverse such as kinasescyclin- dependentsuch as cyclin-dependent kinase 5 (CDK5) kinase [14] 5 (CDK5) and glycogen [14] and glycogensynthase synthasekinase-3beta kinase-3beta (GSK-3 (GSK-3β) [15].β )[Tau15]. hyperphosphorylationTau hyperphosphorylation could could be maintained be maintained by bya fa ailure failure of ofactivation activation of of phosphatase phosphatase like like protein phosphatase 2A (PP2A) [16]. [16]. Hyper- Hyper-phosphorylatedphosphorylated tau tau aggregates aggregates into into neurofibrillary neurofibrillary tangles tangles (NFTs). (NFTs). 2+ 2+ 3+ 2+ 2+ 2+ 2+ 2+ 3+ Zn2+, ,Cu Cu2+, Fe, Fe3+, Mg, Mg2+, Mn,2+ Mn, Pb2+, Cd Pb2+, ,Hg Cd2+, and, Hg Al3+, andpromote Al taupromote hyperphosphorylation tau hyperphosphorylation and induce andtau 2+ 2+ aggregationinduce tau aggregation(red arrow). (redIn contrast, arrow). Fe In2+, contrast,and Li2+ reduce Fe , andtau hyperphosphorylation Li reduce tau hyperphosphorylation (blue arrow). For further(blue arrow). details Forand further references details on metal and references ions effect on (see metal Table ions 1). effect (see Table1). 2. Essential Biometal Ions 2.1. Zinc Zinc is an important metal ion in the body that regulates synaptic transmission, brain development, and immune function [17–19]. Physiological concentrations of zinc in the human brain range from 56.7 to 75.9 μg/g [20]. Clinical studies report an increase of brain levels of zinc at a significantly higher range of 62.0 to 89.9 μg/g in AD patients compared to age-matched control subjects. Zinc dyshomeostasis in the brain is linked with multiple neurotoxic implications as it can potentially trigger neuronal injury and severely worsen the pathogenesis of neurodegenerative diseases. In addition to studies detailing zinc-induced neuronal injury and cell death, researchers have also been looking at how an imbalance of brain zinc levels can serve as a contributing factor to Int. J. Mol. Sci. 2018, 19, 128 3 of 15 2. Essential Biometal Ions 2.1. Zinc Zinc is an important metal ion in the body that regulates synaptic transmission, brain development, and immune function [17–19]. Physiological concentrations of zinc in the human brain range from 56.7 to 75.9 µg/g [20]. Clinical studies report an increase
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