Iron (III) induces aggregation of hyperphosphorylated τ and its reduction to iron (II) reverses the aggregation: implications in the formation of neurofibrillary tangles of Alzheimer's disease

Abstract

Iron as well as aluminum is reported to accumulate in neurons with neurofibrillary tangles (NFTs) of Alzheimer's disease (AD) brain. Previously we demonstrated that aluminum (III) shows phosphate-dependent binding with hyperphosphorylated s (PHFs), the major constituent of NFTs, thereby inducing aggregation of PHFs. Herein we report that iron (III) can also induce aggregation of soluble PHFs. Importantly, for the aggregation of PHFs to occur, iron in the oxidized state (III) is essential since iron in the reduced state (II) lacks such ability. Furthermore, iron (III)-induced aggregation is reversed by reducing iron (III) to iron (II). Thus the iron-participating aggregation is mediated not only by s phosphorylation but also by the transition of iron between reduced (II) and oxidized (III) states. Further incubation of insoluble PHFs aggregates isolated from AD brain with reducing agents produced liberation of solubilized PHFs and iron (II), indicating that PHFs in association with iron (III) constitutes the insoluble pool of PHFs. These results indicate that iron might play a role in the aggregation of PHFs leading to the formation of NFTs in AD brain. Keywords: aluminum, Alzheimer's disease, iron, phosphorylation, protein aggregation, s protein. One of the major histopathologic abnormalities of brains with Alzheimer's disease (AD) is the neurofibrillary lesions consisting of neurofibrillary tangles (NFTs), dystrophic neurites associated with senile plaques, and neuropil threads (Goedert et al. 1997). These lesions contain filamentous structures called paired helical filaments (PHFs) and related straight filaments, which are formed from the microtubuleassociated protein s of the CNS. s constituting the PHFs, often referred to as PHFs, is characterized by several posttranslational protein modifications. In the normal adult brain, s is dynamically phosphorylated to a state resulting from balanced activities of protein kinases and phosphatases, while in AD brain s is in a highly and stably sustained state of phosphorylation (Matsuo et al. 1994). Another prominent feature of PHFs is its ability to form insoluble aggregates, in contrast to the unusual solubility of normal s (Cleveland et al. 1977;Lee et al. 1988).To understand the mechanism(s) involved in the formation of NFTs, it is important to know the causal relationship between phosphorylation and aggregation of s. In the brain the association of s with microtubules is normally regulated by altering its phosphorylation state; s in a non-phosphorylated form associates with microtubules and, on phosphorylation, dissociates from microtubules (Drechsel et al. 1992).In AD brain hyperphosphorylated s shows diminished Received May 9, 2002; accepted May 15, 2002. Address correspondence and reprint requests to Ryong-Woon Shin, Department of Neurological Science, Tohoku University School of Medicine, 2-1 Seiryo-machi, Sendai 980-8575, Japan. E-mail: shin@mail.cc.tohoku.ac.jpAbbreviations used: AD, Alzheimer's disease; BCIP, 5-bromo-4-chloro-3-indolylphophate p-t...

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