DIFFERENTIAL EFFECTS OF ALUMINUM AND LITHIUM ON LPS AND A β‐(25–35) INDUCED INOS GENE EXPRESSION IN GLIA AND IN TAU HYPER‐PHOSPHORYLATION, AND ON NEURITE INHIBITION.

The etiology of Alzheimer’s disease (AD) is multifactorial . It has been suggested that transition metals such as copper and Aluminum (Al) may be involved in the pathogenesis of this disorder. In our previous studies we demonstrated the role of LPS/Aβ‐induced signal transduction cascades in induction of iNOS. Here in this study we examined the effect of Lithium (Li) and Aluminum (10 μM each) on LPS/Aβ‐induced iNOS gene expression and nitric oxide release, possible activation of Pkb/Akt & ERK signaling cascades, and redox alterations in glial cells. We also investigated the effect of these metals on ’Tau’ phosphorylation in N2a neuronal cell line under inflammatory conditions , and neurite outgrowth inhibition in NGF differentiated PC‐12 cells. Results: LPS/Aβ mediated induction of iNOS gene expression and nitric oxide release were upregulated upon Lithium treatment. However, in contrast Al treatment downregulated these effects. Studies performed to examine the neurotoxic activities of both Al and Li in N2a neuroblastoma cell line, showed enhanced ‘Tau’ phosphorylation upon incubation with Al and Li in the presence of cytokines. Further examination of redox regulators such as MnSOD,Cu/ZnSOD and Catalase gene expression under similar conditions of treatment demonstrated an alteration in these enzyme gene expression, in favour of enhanced oxidative stress, which all suggests to the neurotoxic nature of both these metals under neuroinflammatory situations.