Mechanisms of aluminium neurotoxicity in oxidative stress-induced ...

INTRODUCTION
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The signal transduction pathway of mitogen-activated protein kinase (MAPK)
plays also an important role in the apoptosis in neurons or astrocytes. Aluminium was
demonstrated to activate in cultured cortical neurons one of the important members in
MAPK family, the stress-activated protein kinase c-jun N-terminal kinase (SAPK/JNK)
(Fu et al. 2003), whose phosphorylation and dephosphorylation are considered as the
molecular key in stress signal transduction. SAPK/KNK activates its downstream
transcription factor c-jun, which is the important component of AP-1. This latter
modulates the expression of target genes and participates in the regulation of cell
differentiation and apoptosis.
Neuronal accumulation of aluminium affects mitochondria integrity and
functionality (reviewed by Kumar and Gill 2009). The metal enters into the neuron
upon cell depolarization and inhibits Na + /Ca 2+ exchange thus inducing an extreme
accumulation of mitochondrial Ca 2+ . This triggers the opening of the mitochondrial
transition pore (MTP) and the consequent release of cytochrome c leading finally to
activation of the caspase family proteases. Studies that used intracisternal injection of
the aluminium-maltolate complex have shown that aluminium targets mitochondria.
Aluminium-maltolate is a lipophilic complex stable at physiological pH and proposed to
be formed in the gastrointestinal tract. This neurotoxic complex produces cytoskeletal
alterations (Klatzo et al. 1965, Savory et al. 1996, 1998) leading to tangle formation and
cell apoptosis (Johnson et al. 2005). Aluminium-maltolate induces cytochrome c
translocation, increased expression of the proapoptotic protein Bax, and decreased
expression of the antiapoptotic protein Bcl-2, finally leading to cell apoptosis (Ghribi et
al. 2001a, 2002).
In addition, aluminium also affects the endoplasmic reticulum (ER), the major
storage location for calcium, which also contains members of the Bcl-2 family, such as
Bcl-2 and Bcl-XL. The stress induced by aluminium-maltolate activates caspase 12
leading to a specific type of ER-mediated cell death by apoptosis (Ghribi et al. 2001b,
2001c, 2002).