Can the mechanisms of aluminum neurotoxicity be integrated into a unified scheme?
Regardless of the host, the route of administration, or the speciation, aluminum is a potent neurotoxicant. In the young adult or developmentally mature host, the neuronal response to Al exposure can be dichotomized on morphological grounds. In one, intraneuronal neurofilamentous aggregates are formed, whereas in the other, significant neurochemical and neurophysiological perturbations are induced without neurofilamentous aggregate formation. Evidence is presented that the induction of neurofilamentous aggregates is a consequence of alterations in the posttranslational processing of neurofilament (NF), particularly with regard to phosphorylation state. Although Al has been reported to impact on gene expression, this does not appear to be critical to the induction of cytoskeletal pathology. In hosts responding to Al exposure without the induction of cytoskeletal pathology, impairments in glucose utilization, agonist-stimulated inositol phosphate accumulation, free radical-mediated cytotoxicity, lipid peroxidation, reduced cholinergic function, and altered protein phosphorylation have been described. The extent to which these neurochemical modifications correlate with the induction of a characteristic neurobehavioral state is unknown. In addition to these paradigms, Al is toxic in the immediate postnatal interval. Whether unique mechanisms of toxicity are involved during development remains to be determined. In this article, the mechanisms of Al neurotoxicity are reviewed and recommendations are put forth with regard to future research. Primary among these is the determination of the molecular site of Al toxicity, and whether this is based on Al substitution for divalent metals in a number of biological processes. Encompassed within this is the need to further understand the genesis of host- and developmental-specific responses.
Strong
M J
MJ
Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada. mstrong@julian.uwo.ca
Garruto
R M
RM
Joshi
J G
JG
Mundy
W R
WR
Shafer
T J
TJ
D000328:Adult; D000535:Aluminum / Q000009:adverse effects* / Q000493:pharmacokinetics; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects* / Q000503:physiopathology; D003599:Cytoskeleton / Q000187:drug effects / Q000473:pathology; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D006801:Humans; D008660:Metabolism / Q000187:drug effects; D009448:Neurochemistry / Q000379:methods; D009482:Neurophysiology / Q000379:methods; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D012107:Research Design
D000535:Aluminum