The etiology of neurodegenerative disorders is at present unknown. However, many of these disorders are associated with an increase in oxidative and inflammatory events. Although a small percentage of these disorders are familial cases linked to specific genetic defects, most are idiopathic. Thus, environmental factors are thought to play an important role in the onset and progression of such disorders. We have demonstrated that exposure (4 h, 5 days per week for 2 weeks) to concentrated airborne particulate matter increases inflammatory indices in brain of ovalbumin-sensitized BALB/c mice. Animals were divided into three exposure groups: filtered air (control), ultrafine particles, or fine and ultrafine particles. The levels of proinflammatory cytokines interleukin-1 alpha (IL-1alpha) and tumor necrosis factor alpha (TNF-alpha) were increased in brain tissue of mice exposed to particulate matter compared to that of control animals. Levels of the immune-related transcription factor NF-kappaB were also found to be substantially elevated in the brain of exposed groups compared with the control group. These data indicate that components of inhaled particulate matter may trigger a proinflammatory response in nervous tissue that could contribute to the pathophysiology of neurodegenerative diseases.

Although aluminum is the most abundant metal in nature, it has no known biological function. However, it is known that there is a causal role for aluminum in dialysis encephalopathy, microcytic anemia, and osteomalacia. Aluminum has also been proposed to play a role in the pathogenesis of Alzheimer's disease (AD) even though this issue is controversial. The exact mechanism of aluminum toxicity is not known but accumulating evidence suggests that the metal can potentiate oxidative and inflammatory events, eventually leading to tissue damage. This review encompasses the general toxicology of aluminum with emphasis on the potential mechanisms by which it may accelerate the progression of chronic age-related neurodegenerative disorders.

A link between aluminum (Al) exposure and age-related neurological disorders has long been proposed. Although the exact mechanism by which the metal may influence disease processes is unknown, there is evidence that exposure to Al causes an increase in both oxidative stress and inflammatory events. These processes have also been suggested to play a role in Alzheimer's disease (AD), and exposure to the metal may contribute to the disorder by potentiating these events. Al lactate (0.01, 0.1, and 1 mM) in drinking water for 10 weeks increased inflammatory processes in the brains of mice. The lowest of these levels is in the range found to increase the prevalence of AD in regions where the concentrations of the metal are elevated in residential drinking water (Flaten [2001] Brain Res. Bull. 55:187-196). Nuclear factor-kappaB as well as tumor necrosis factor-alpha (TNF-alpha) and interleukin 1alpha (IL-1alpha) levels were increased in the brains of treated animals. The mRNA for TNF-alpha was also up-regulated following treatment. Enhancement of glial fibrillary acidic protein levels and reactive microglia was seen in the striatum of Al-treated animals. The level of amyloid beta (Abeta40) was not significantly altered in the brains of exposed animals. Insofar as no parallel changes were observed in the serum or liver of treated animals, the proinflammatory effects of the metal may be selective to the brain. Al exposure may not be sufficient to cause abnormal production of the principal component of senile plaques directly but does exacerbate underlying events associated with brain aging and thus could contribute to progression of neurodegeneration.

Inflammatory and oxidative events are up-regulated in the brain of AD patients. It has been reported that in animal models of AD, exposure to aluminum (Al) or copper (Cu) enhanced oxidative events and accumulation of amyloid beta (Ah) peptides. The present study was designed to evaluate the effect of a 3-month exposure of mice to copper sulfate (8 AM), aluminum lactate (10 or 100 AM), or a combination of the salts. Results suggest that although Al or Cu may independently initiate inflammatory or oxidative events, they may function cooperatively to increase APP levels. D

Abstract. The etiology of Alzheimer's Disease (AD) is multifactorial. It has been suggested that transition metals such as copper (Cu) and iron (Fe) as well as aluminum (Al) may be involved in the pathogenesis of the disorder. While Cu and Fe are redox-active, Al only exists in the trivalent form and is redox-inert. We previously demonstrated that Al exposure causes an increase in inflammatory parameters in human glioblastoma T98G cells. In the present study we further demonstrate that co-exposure with Cu exacerbates the oxidative but not inflammatory effects of Al in this cell line. While Cu-induced reactive oxygen species (ROS) production was greatly enhanced in the presence of Al, TNF-a secretion induced by either metal was not further potentiated by simultaneous exposure to Al and Cu. Furthermore, exposure to both metals reduced the individual Al and Cu-induced activation of the immune-related transcription factor NF-,,,;B. Therefore, while synergistic interaction between the two metals increases oxidative events, this does not lead to potentiation of Al-induced inflammation. Thus the ability of aluminum to promote inflammatory processes does not depend on an increase ROS production induced by interaction with transition metals.

Cells rely on several transition metals to regulate a wide range of metabolic and signaling functions. The diversity and efficiency of their physiological functions are derived from atomic properties that are specific to transition metals, most notably an incomplete inner valence subshell. These properties impart upon these elements the ability to fluctuate among a variety of positively charged ionic forms, and a chemical flexibility that allows them to impose conformational changes upon the proteins to which they bind. By this means, transition metals can serve as the catalytic centers of enzymes for redox reactions including molecular oxygen and endogenous peroxides. This review addresses the consequences of the aberrant translocation of the redox-capable essential transition elements, iron, copper, and manganese, upon the brain with an emphasis on uncontrolled and deleterious oxidative events. The potential of metal-protein interactions in facilitating such events, and their association with the physiologically redox-inert metals zinc and aluminum, are related to their postulated contribution to the pathology of neurodegeneration.

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