Aluminium-induced synaptic plasticity injury via the PHF8–H3K9me2-BDNF signalling pathway
Graphical abstract
Introduction
Aluminium is the third most abundant element in the Earth’s crust, comprising up to about 8% of the Earth’s surface (Williams, 1997). In the natural environment, PM < 2.5 aluminium levels are in the range of 0.035–1.82 μg/m3 (excluding sites in the Arctic and Antarctica) and PM10 in the range of 0.58–6.97 μg/m3; aluminium has an oral reference dose of 1 mg/kg day−1. Food comprises more than ninety percent (90%) of the non-occupational human exposure to aluminium (Kandimalla et al., 2016). A large number of previous studies have shown that aluminium’s effect on the damage of the nervous system is often reflected by its close correlation with various neurodegenerative diseases, most commonly with Alzheimer’s diseases (AD), amyotrophic lateral sclerosis (ALS), and dialysis encephalopathy (Krewski et al., 2007). The relationship between aluminium exposure and AD has been the focus of intense research, and epidemiological investigations have found a strong correlation between the accumulation of aluminium in the brain and AD, both for workers occupationally exposed to aluminium and for people who drink tap water that might contain higher aluminium content after being purified with aluminium salts or due to the geographical location (Flaten, 2001; Polizzi et al., 2002; Bakar et al., 2009). The decline in the cognitive impairment in AD patients is one of the main manifestations of this disease. Interestingly, previous studies have shown that the main neurotoxic effect of occupational aluminium exposure on workers was cognitive impairment(Petrik et al., 2007; Tomljenovic and Shaw, 2011).
The hippocampus, is an important research target and model for exploring the cell and molecular mechanisms of learning and memory and exhibits, synaptic plasticity changes during these processes. Many neuroscientists have used the hippocampus in in vivo and in vitro experiments to explore cognitive function and the roles of cognitive function-related molecules (Norman, 2010; Yang et al., 2014). In the mammalian brain, NMDA receptor-dependent LTP and long-term depression (LTD) of synaptic transmission are the two major forms of synaptic plasticity, which have been studied in detail in the CA1 region of the hippocampus. The most widely studied example of synaptic plasticity is hippocampal LTP, which is induced by a brief, but intense stimulus, resulting in synaptic strengthening(Malenka and Bear, 2004). Since Bliss and Lomo(Bliss and Lomo, 1973) described the phenomenon of LTP, as one of the manifestations of synaptic plasticity, many scholars, such as Gruart (Gruart et al., 2006) and Lynch (Lynch et al., 2014), have proved that synaptic plasticity is the molecular basis of learning and memory, and LTP has been widely used as an important indicator of learning and memory variations.
Histone methylation modification plays an important role in the process of gene transcriptional activation and inhibition(Martin and Zhang, 2005), and the role of histone modification in learning and memory has gradually become a prevailing research topic in the field of neurology. Histone-lysine methylation is a reversible reaction catalysed by histone lysine methyltransferases (HKMTs) and reversed by histone demethylases (Feng et al., 2010). Histone H3 lysine 4(H3K4), Histone H3 lysine 36 (H3K36) and Histone H3 lysine 79 (H3K79) are involved in transcriptional activation, while Histone H3 lysine 9 (H3K9) and Histone H3 lysine 27 (H3K27) are involved in transcriptional inhibition (Upadhyay and Cheng, 2010). H3K9me2, a covalent histone modification, is considered as a marker of gene transcriptional silencing (Stewart et al., 2005), and often recruits Heterochromatin Protein 1 (HP1) to interfere with histone acetylation resulting in transcriptional inhibition (Hiragami and Festenstein, 2005). PHF8, a member of Jumonji C(JmjC) domain-containing protein family, has been proved to have specific demethylase activity against H3K9me2 by structural biology analysis (Zhu et al., 2010). Studies have shown that Al3+ binds to proteins in some enzymes containing Zn2+, replacing zinc ions (Di et al., 2006; Chakraborty and Basak, 2008). Another study performed " in vitro " and " in vivo " demonstrated that Al3+ may induce a complex perturbation in Zn-dependent enzymes, modifying their interactions with other toxic metals: antagonistic effects of Zn and Al on Pb inhibition of delta-ALAD (a Zn dependent enzyme) were evidenced(Svensson and Haeger, 1979). In addition to the JmjC domain, PHF8 also contains a plant homeodomain (PHD) (Fortschegger et al., 2010). PHD, an atypical zinc finger structure, needs to bind two Zn2+ and demethylation of this enzyme requires the joint participation of Fe2+ (Yue et al., 2010). Therefore, our hypothesis is that Al3+ may interfere with the zinc finger structure of PHD and the Fe2+ present in PHF8, thus affecting the normal functioning of the enzyme. Thereafter, the demethylation process of H3K9me2 is blocked, resulting in high expression of the H3K9me2 protein.
BDNF is mainly synthesised in the brain and is expressed highly in the cerebral cortex, hippocampus and other parts of the brain. As a key factor, of synaptic plasticity maintenance, BDNF can act on receptors in the hippocampus and other brain regions related to learning and memory, and enhance the synaptic transmission efficiency by strengthening the activity of neurotransmitters and receptors related to these processes (Gupta et al., 2010; Autry and Monteggia, 2012; Cascante et al., 2014; Ninan, 2014). Studies on BDNF have shown that it can be modified by histone lysine methylation (Zhou et al., 2007). Therefore, we hypothesise that aluminium may induce the change of H3K9me2 expression by interfering with the function of PHF8, and eventually lead to a change in BDNF expression, which can have an impact on hippocampal synaptic plasticity and lead to the impairment of learning and memory. We have previously shown that the average of field excitatory postsynaptic potentials (fEPSPs) was decreased at different time points in all exposed groups (2 mg/kg, 12 mg/kg and 72 mg/kg) compared with that of the control group, and that the expression levels of PHF8, BDNF and H3K9me2 were statistically different between controls and the exposed groups (Li et al., 2016).
This study aimed to investigate the possible link, and clarify the underlying mechanisms, between aluminium exposure and LTP impairment in vivo. We investigated the electrophysiology of LTP in the rat hippocampal CA1 region, and measured PHF8 enzyme activity, PHF8 gene expression, and the protein expression of PHF8, H3K9me2, and BDNF in the hippocampus, to elucidate whether aluminium-induced impairment of LTP via the PHF8–H3K9me2-BDNF signalling pathway.
Section snippets
Reagents
The reagents used in this study are listed below along with their providers. Aluminium trichloride, urethane, hydrogen peroxide, sodium chloride (Tianjin Fengchuan Chemical Reagent Technology co., LTD.); EpiQuik Nuclear Extraction Kit I Kit (Epigentek, USA); Brandford protein quantitative kit (Bokeling, Beijing); H3K9 demethylase activity detection kit (Abnova, Taiwan); total protein extraction kit, diquinoline formic acid (BCA), loading buffer, protein quantitative kit, high sensitivity
AlCl3 treatment significantly suppressed LTP in the hippocampal CA1 region
To examine the possible alterations in LTP when rats were exposed to AlCl3, we induced LTP in the hippocampal CA1 area by applying HFS comprised of 20 pulses at 200 Hz each (Fig. 1). The standardised fEPSP amplitude increased in both the control group and the aluminium exposed group, and LTP was found to be dose-dependent inhibited(a1,b1,c1,d1). As shown in Fig.a2, the fEPSP amplitude in the control group was 252.60 ± 3.09, 227.89 ± 4.27 and 222.43 ± 3.79% at 1, 30 and 60 min after HFS
Discussion
Gitelman (1995) and Gitelman et al. (1995) conducted a survey involving 40 control subjects and 235 workers employed in 15 plants in the USA engaged in primary and secondary aluminium refining and in the manufacturing of products. Personal exposures ranged from 0.01 to 1.20 mg/m3, with a median of 0.025 mg/m3 for respirable fractions (<10 μm), and 0.001–3.0 mg/m3 with a median of 0.10 mg/m3 for the “total” aerosol fractions. Our research group used The World Health Organization recommended
Funding information
This work was supported by the National Natural Science Foundation of China [No. 81430078].
Author contribution section
Huan Li: Data curation, Formal analysis, Writing - Original Draft, Writing - Review, Xingli Xue: Formal analysis, Zhaoyang Li: Formal analysis, Baolong Pan: Validation, Yanxia Hao: Validation, Qiao Niu: Conceptualization, Writing -Editing, Funding acquisition.
Declaration of competing interest
The authors declare that there are no conflicts of interest.
Acknowledgments
This research was financially supported by the National Natural Science Foundation of China [No. 81430078]. We sincerely thank colleagues for their help and work on the research.
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