Molecular mechanisms of aluminum neurotoxicity: Update on adverse effects and therapeutic strategies

Aluminum (Al) is considered as the most abundant metal in the Earth’s crust, being the third most abundant chemical element after oxygen and silicon. Intensive development of the Al industry (Brough and Jouhara, 2020) due to a wide use of the metal has resulted in a significant increase in environmental Al levels (Crisponi et al., 2012). The sources of human Al exposure may include diet (Tietz et al., 2019), being responsible for 95% of total body Al (Goulle and Grangeot-Keros, 2020), drinking water (Krupinska, 2020), air (Exley, 2013), as well as cosmetics (Crisponi et al., 2012, 2013) and medicinal drugs, namely antacids (Klotz et al., 2017). Involvement in Al processing industry may also result in occupational Al exposure (Skalny et al., 2018). Earlier studies demonstrated that vaccination could be considered as a source of Al exposure due to the presence of aluminium adjuvants that are currently not widely used thus reducing the risk of vaccine-associated Al exposure (Goulle and Grangeot-Keros, 2020). Being a non-essential element, Al was shown to be toxic for humans (Exley, 2013), resulting in adverse health effects (Crisponi et al., 2011) including bone pathology (Klein, 2019) and breast cancer (Darbre et al., 2013). Our data also demonstrated the association between obesity (Tinkov et al., 2019), laboratory markers of metabolic syndrome and Al exposure markers (Skalnaya et al., 2018). However, the existing data on adverse effects of Al exposure are limited (Krewski et al., 2007). Recent studies have demonstrated that the brain may be considered as the target for Al toxicity (Exley, 2014), resulting in neurodegenerative (Exley, 2013; Shaw et al., 2014) and neurodevelopmental disorders (Blaylock, 2012). Recent detailed studies by Exley and the coauthors have highlighted the association between brain Al accumulation and neurological disorders including Alzheimer’s disease, multiple sclerosis and autism spectrum disorder (Exley and Clarkson, 2020; Mirza et al., 2017; Mold et al., 2018). Speciation analysis using hyphenated techniques demonstrated that Al exposure induces a specific bioligand response in Al-exposed neuronal cells (Polec-Pawlak et al., 2004). However, the particular mechanisms of Al neurotoxicity and their role in Al-associated neurological disorders are still debatable (Morris et al., 2017). This chapter will provide an update on the particular mechanisms of Al neurotoxicity that may be used as targets for development of therapeutic strategies. Generally, the neurotoxic effect of Al exposure is mediated by its common toxic properties including prooxidant, proinflammatory, proapoptotic activity that are reported for a variety of cell lines and tissues, as well as more specific “neurotropic” effects namely interference with neurotransmitter metabolism and neuronal cytoskeleton.