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Zinc Transporters in Alzheimer's Disease

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Zinc Transporters in Alzheimer's Disease Xu et al. Molecular Brain (2019) 12:106 https://doi.org/10.1186/s13041-019-0528-2 REVIEW Open Access Zinc transporters in Alzheimer’s disease Yingshuo Xu1, Guiran Xiao2, Li Liu3 and Minglin Lang1,4* Abstract Alzheimer’s disease (AD) is the most devastating neurodegenerative disorder. Due to the increase in population and longevity, incidence will triple by the middle of the twenty-first century. So far, no treatment has prevented or reversed the disease. More than 20 years of multidisciplinary studies have shown that brain zinc dyshomeostasis may play a critical role in AD progression, which provides encouraging clues for metal-targeted therapies in the treatment of AD. Unfortunately, the pilot clinical application of zinc chelator and/or ionophore strategy, such as the use of quinoline-based compounds, namely clioquinol and PBT2, has not yet been successful. The emerging findings revealed a list of key zinc transporters whose mRNA or protein levels were abnormally altered at different stages of AD brains. Furthermore, specifically modulating the expression of some of the zinc transporters in the central nervous system through genetic methods slowed down or prevented AD progression in animal models, resulting in significantly improved cognitive performance, movement, and prolonged lifespan. Although the underlying molecular mechanisms are not yet fully understood, it shed new light on the treatment or prevention of the disease. This review considers recent advances regarding AD, zinc and zinc transporters, recapitulating their relationships in extending our current understanding of the disease amelioration effects of zinc transport proteins as potential therapeutic targets to cure AD, and it may also provide new insights to identify novel therapeutic strategies for ageing and other neurodegenerative diseases, such as Huntington’s and Parkinson’s disease. Keywords: Zinc transporter, Brain, Genetic modulation, Emerging therapeutic target, Alzheimer’s disease, Ageing Introduction Considerable early clinical studies, including pharmaceut- Alzheimer’s disease (AD) is a progressive neurodegenera- ical approaches designed to change the level of zinc or to tive disease, which leaves many elderly people cognitively alter the distribution of zinc and copper, have provided impaired [1] and the numbers are expected to reach 131 encouraging clues for metal-targeted therapies in the million by 2050 [2]. The disorder is characterized by a treatment and prevention of AD [9–11]. progressive loss of memory due to the degeneration and/ Zinc metabolism is firmly controlled by zinc transporters or loss of neurons related to cognition in the hippocampus that transport zinc through the membrane to the cyto- and cortex. Pathologically, the extracellular accumulation plasm or organelles and maintain zinc homeostasis both at of amyloid plaques rich in the β-amyloid (Aβ) peptide and the cellular and systemic levels. Zinc transporters are clas- intracellular deposition of neurofibrillary tangles (NFTs) sified into two families: the ZnT (SLC30) family and the with hyperphosphorylated tau in the brain are the two ZIP (SLC39) family. To the best of our knowledge, most major hallmarks of AD [3, 4]. Aβ aggregates can form zinc transporters are also expressed in mammalian brains, complexes with redox active metals, and the phosphoryl- such as ZnT1, ZnT3, ZnT10, ZIP1 and ZIP6 [12–17]. ation of tau is also associated with metals [5], especially Moreover, it has been established that a considerable num- zinc, which interplays with the Aβ protein, aggravating the ber of zinc transporters were abnormally expressed in the precipitation of senile plaques, and it can also bind to tau brains of AD patients and APP/PS1 mice [18–20], suggest- proteins, contributing to the formation of NFTs [6–8]. ing that zinc transporters may play a critical role in the progression of AD. Since so far there has been no effective * Correspondence: [email protected] therapy to halt or reverse AD, we propose that altering zinc 1CAS Center for Excellence in Biotic Interactions, College of Life Science, homeostasis by modulating the expression or capability of University of Chinese Academy of Sciences, Beijing 100049, China zinc transporters may be a better way to ameliorate AD. 4College of Life Science, Hebei Agricultural University, Baoding 071001, China Full list of author information is available at the end of the article This review focuses first on the relationship between zinc © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Xu et al. Molecular Brain (2019) 12:106 Page 2 of 12 transporters and AD. After that, we summarize the func- zinc overload also include reduced cellular ATP levels and tion of zinc transporters that are involved in brain zinc loss of mitochondrial membrane potential [35]. A later homeostasis and assess recent evidence for treating AD study through direct biochemical assays demonstrated with the alteration of zinc transporters. that excess zinc can irreversibly damage the major en- zymes of energy production and antioxidant defense prior The important role of zinc in the brain to mitochondrial permeability transition [36]. Zinc will As an indispensable trace element, zinc is a structural or participate in numerous signal transduction processes as functional component of many proteins. It also partici- soon as it enters the postsynaptic neuron, and as a neuro- pates in various physiological functions, including but modulator, zinc can influence the brain excitability by not limited to DNA synthesis, brain development and inhibiting excitatory and inhibitory receptors, thus Zn2+ neurotransmission [21–23]. Considering its multifaceted qualifying as both a neurotransmitter and a second mes- role in biological processes, alterations in zinc concen- senger [37]. trations from normal levels can induce many devastating On the other hand, zinc can modulate synaptic plasticity diseases, e.g., zinc deficiency leading to mental lethargy, in the form of long-term potentiation (LTP) and long-term growth retardation and immune dysfunction, while zinc depression (LTD), respectively, which are considered to be overload can affect the function of lymphocytes and underlying learning and memory, and are differentially cause copper deficiency [24]. modulated by NMDA receptor subunits [37–39]. When Besides the important role of zinc in normal mamma- stimulated, zinc is co-released with glutamate into the syn- lian brain development and physiology [25], it also plays a aptic cleft to modulate the activity of post-synaptic pro- critical role in the function of the central nervous system teins, NMDA and AMPA receptors. Simultaneously, zinc (CNS). There are three pools of zinc in the brain, namely can transactivate the tropomyosin-related kinase B (TrkB) vesicular zinc, protein-bound zinc and free zinc [26]. Ves- receptor in cultured cortical neurons. As soon as zinc icular zinc exists mainly in glutamatergic neurons, but not enters the postsynaptic neuron, it activates brain-derived all glutamatergic neurons contain zinc [27, 28]. Studies neurotrophic factor (BDNF) signaling in a neurotrophin- found that zinc can permeate through the neuronal mem- independent manner [40, 41]. Zinc can also affect BDNF brane via several ion channels, such as Ca2+-permeable α- signaling by promoting maturation of pro-BDNF to BDNF amino-3-hydroxyl-5-methyl-4-isoxazolepropionate-acid all through the activation of matrix metalloproteinases (AMPA) /kainite (Ca2+-A/K) channels [29], high-voltage (MMPs), thereby significantly increasing BDNF level in activated (HVA) Ca2+ channels [30], and N-methyl-D-as- brains of AD mice and greatly delaying hippocampal- partate (NMDA) receptor-gated channels [31], depending dependent memory deficits [42]. A subsequent study has on neuronal stimulation. Zinc binds to the extracellular shown that under physiological conditions, it is BDNF amino-terminal domain (ATD) of NMDA receptors [32], rather than vesicular zinc that activates TrkB in hippocam- and activation of AMPA and NMDA receptors facilitated pal mossy fiber axons [43]. Synaptic release of Zn2+ ac- Zn2+ influx into neurons [31, 33]. Zinc can also enter neu- tivates a Zn2+-sensing receptor, mZnR/GPR39, induces rons through voltage-gated calcium channels, especially Ca2+-signaling, then activates ERK1/2 MAPK and up- when the pH is lower [30]. Toxic activation studies have regulates clusterin; however, Zn2+ signaling via mZnR/ shown that Ca2+-A/K channels can carry a greater flux of GPR39 is disrupted by amyloid-β in AD brains, which zinc than influx of zinc in comparison with voltage- is a critical pathological component of AD [44]. Such a sensitive Ca2+ channel (VSCCs) and NMDA channels, and vital role of zinc in the brain has prompted the scien- the permeability of Ca2+-A/K channels to zinc is also com- tific community to continue exploring the etiology and parable to their permeability for Ca2+ [29]. Because they therapeutic strategies based on zinc dyshomeostasis
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