Characterizing the molecular mechanisms underlying aluminium-induced disruptions in neuronal survival pathways

Aluminium, an omnipresent environmental pollutant, has been recognized for its neurotoxic effects, particularly its ability to promote neuronal death. More research evidence links aluminium exposure to death through molecular mechanisms. This review delves into the mechanisms underlying aluminium-induced neurotoxicity, including programmed cell death pathways such as apoptosis, necroptosis, autophagy, ferroptosis, and pyroptosis. Aluminium exposure leads to disruption of oxidative homeostasis and induction of endoplasmic reticulum stress, mitochondrial dysfunction and DNA damage, which in turn trigger different cell death pathways. Substantial changes in key signalling pathways, such as the IL-1β/JNK, PI3K/Akt/mTOR, Nrf2/Ho-1, System Xc-/GPX4, and NLRP3 inflammasome activation pathways, were observed. Overall, these intertwined pathways highlight aluminium as a potent modulator of neuronal survival pathways, driving neurodegeneration through multifactorial mechanisms. A thorough understanding of these changes provides a fundamental explanation of the role of aluminium toxicity in the etiology of neurodegenerative diseases and provides a foundation for treatment.