Zinc transporters in Alzheimer's disease

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: Ageing; Alzheimer’s disease; Brain; Emerging therapeutic target; Genetic modulation; Zinc transporter.

Fig. 1

An overview of the locations of some crucial zinc transporters in mammalian cells and the intracellular and intercellular compartmentation of zinc ions. Zinc transporters are classified into two major families, the ZnT (SLC30) family and the ZIP (SLC39) family. As indicated by arrows in the figure, the general functions of ZnTs (ZnT1–7) is to reduce cytoplasmic zinc levels through mobilization of zinc out of cells or into intracellular compartments from the cytoplasm, whereas the function of ZiPs (ZiP1, ZiP4, ZiP6, ZiP8–10, ZiP13–14) is to increase cytoplasmic zinc levels through absorbing zinc into cytoplasm from extracellular space or mobilizing zinc out of intracellular compartments

Fig. 2

Schematic depiction of the major altered expression of zinc transporters in the neurons of developing AD. Exchangeable zinc ions across the blood-brain barrier/blood-CSF barrier by binding with His or Cys to form Zn (His)² or Zn (Cys)(His)⁻, and then the complex is transferred into or out of the glial cells and neurons through zinc-binding proteins (ZIPs, ZnTs and DMT1). However, in AD patients, the expression levels of some major zinc transporters are altered, and this exacerbates Aβ deposition and toxicity. As shown in the figure, the highly upregulated ZnT1 pumps more zinc from presynaptic neurons and glial cells, which aggravates the deposition of Aβ proteins, and with the lower available zinc ions in the neuronal cytoplasm, upregulation of ZIP1 expression is induced to import zinc from the extracellular milieu to sustain the normal zinc homeostasis. However, this leads to a vicious cycle. In addition, the decreased expression level of ZnT3 leads to insufficient release of zinc into the cleft, and thus the inhibitory function of zinc on NMDAR will be impaired; as a result, more Ca²⁺ enters the postsynaptic cells, leading to apoptosis and cognitive disorders

Fig. 3

Modifying dZIP1 levels markedly influences the brain Aβ42 fibril deposition and lifespan in a Drosophila AD model. a-b Thioflavin-S (TS) staining was used to detect Aβ42 fibril deposits (bright green dots) in fly brains. Few deposits were found in the control brains (Elav-Gal4, top left) at 25 days after eclosion (dae). TS-positive deposits were found after Aβ42 expression in fly brains (Elav-Gal4 > UAS-Aβ42) at both a 25 and b 30 dae. c The quantitative content of Aβ42 deposits was summarized and expressed after normalization to 25-day old Aβ42 flies. The increase in Aβ42 deposits was age-dependent. Overexpression of dZIP1 in Aβ42-expressing brains (Elav-Gal4 > UAS-Aβ42/UAS-dZIP1) significantly increased fibril deposits at 25 dae, which was higher than 30 dae Aβ42 flies. However, inhibition of dZIP1 (Elav-Gal4 > UAS-Aβ42/UAS-dZIP1 RNAi) dramatically decreased deposit density at 30 dae, which was reduced compared to 25 dae Aβ42 flies. t test, **P < 0.01, ***P < 0.001. Data are expressed as means ± SEM. n = 6 or 8 hemispheres for each genotype. Scale bar: 25 μm. d dZip1 knockdown significantly prolongs the lifespan of Aβ42 flies. The percentage of survivorship was plotted against age (dae). Overexpression of dZIP1significantly shortened the lifespan of Aβ42 (elav-Gal4 > UAS-Aβ42) flies. Decreased dZIP1 levels (Elav-Gal4 > UAS-Aβ42/UAS-dZip1 RNAi) inhibited Aβ42 toxicity in a dose-dependent manner, and dZip1 RNAi #2 showed a more significant phenotype, in which dZip1-RNAi 2# (elav-Gal4 > UAS-Aβ42/UAS-dZip1-RNAi 2#) flies had much more reduced dZIP1 level than that of dZip1-RNAi 1# (elav-Gal4 > UAS-Aβ42/UAS-dZip1-RNAi 1#) flies. The differences shown are all statistically significant (p < 0.001). The reported P values are derived from Mantel-Cox log-rank statistical analysis

Fig. 4

A proposed model illustrating the mechanism of AD progression and amelioration. The expression or alteration in activity of brain zinc transporters induce zinc dyshomeostasis, which aggravate Aß deposition, tau phosphorylation and tau-zinc binding exacerbated toxicity, increasingly promoting neuronal loss (a), while the leading compounds or drugs designed to specifically modify the expression or activity of brain zinc transport proteins have the potential to correct the disturbed zinc metabolism niche, thus leading to reduced Aß deposition, tau dissociation from microtubules and tau toxicity, which ultimately slows or prevents neuronal death in the onset and progression of AD (b)