Molecular mechanisms of aluminium neurotoxicity in animal models of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia that affects one patient every seven seconds. With over 35 million people currently affected worldwide, it has been projected that the disease will affect about 115 million people by 2050. The disease is characterized by dysfunctional cellular and molecular networks and/or genomic and epigenomic interactions that affect the normal function of brain cells, leading to a defective cellular communication and function, and ultimately neurodegeneration. Aluminium (Al³⁺) is the third most abundant ubiquitous element in the earth crust which has gained easy access to humans and extensively used in daily life. It is an essential component of many materials used in households, such as clays, glasses, and alum. An increasing body of evidence implicates Al³⁺ in the progression of events that lead to neurodegenerative diseases, some of which remains controversial, but it is widely accepted that Al³⁺ is a recognised neurotoxin that could cause neurodegenerative diseases such as AD. The pathophysiological changes induced in Al³⁺ neurotoxicity leading to AD result in critical impairments of the central nervous system functions, which are essential for healthy brain ageing. These changes include; axonal transport, neurotransmitter synthesis and synaptic transmission, disruption of calcium homeostasis, alteration of energy metabolism, phosphorylation/dephosphorylation of proteins, protein degradation, gene expression, formation of reactive oxygen species and inflammatory responses, inhibition of DNA repair system, activation of glial cells, reduction of activities of antioxidant enzymes, alterations of pathways of NF-kB and JNK, binding DNA, cell death, motor and cognitive decline. These multi-faceted pathways provide a link between Al neurotoxicity and AD by modulating both tau and amyloid beta hypotheses of AD.

Keywords: Alzheimer’s disease, Aluminium chloride, Amyloid beta, Tau, Animal models