Neurofibrillary pathology and aluminum in Alzheimer's disease

Abstract

Since the first reports of aluminum-induced neurofibrillary degeneration in experimental animals, extensive studies have been performed to clarify the role played by aluminum in the pathogenesis of Alzheimer's disease (AD). Additional evidence implicating aluminum in AD includes elevated levels of aluminum in the AD brain, epidemiological data linking aluminum exposure to AD, and interactions between aluminum and protein components in the pathological lesions of AD, ¡.e., neurofibrillary tangles (NFTs) and senile plaques (SPs). As most of this evidence is circumstantial and some of it is not consistent in al1 reports, the role of aluminum in the pathogenesis of AD has remained controversial. However, the interaction of aluminum with altered forms of t in the paired helical filaments (PHFs) of neurofibrillary lesions is highly likely to contribute to the formation of NFTs because (1) aluminum and abnormally phosphorylated t (known as PHFt) are colocalized in NFTs, and (2) aluminum is known to preferentially interact with such phosphorylated proteins. Recently, we demonstrated that aluminum binds selectively to PHFt, induces PHFt to aggregate, and retards the in vivo proteolysis of PHFt. These data suggest that aluminum could serve as cofactor in the formation of NFTs by interacting with PHFt. This review summarizes current understanding of how aluminum might contribute to the formation of neurofibrillary lesions from PHFt in neurons of the AD brain.