No 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...

No abstract

Increasing evidence suggests that the elevation of ␤-amyloid (A␤) peptides in the brain is central to the pathogenesis of Alzheimer's disease (AD). Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, enhances cAMP/protein kinase A/extracellular signalregulated kinase/cAMP response element-binding protein signaling in cultured hippocampal neurons and ameliorates A␤-induced memory impairment in AD model rats. For the first time, we report that this natural compound improves memory deficits in amyloid precursor protein (APP) transgenic mice that overexpress human APP695 harboring the double Swedish and London mutations [APP-SL 7-5 transgenic (Tg) mice]. Our enzyme-linked immunosorbent assay (ELISA) also showed that administration of nobiletin to the transgenic mice for 4 months markedly reduced quantity of guanidine-soluble A␤ 1-40 and A␤ 1-42 in the brain. Furthermore, consistent with the results of ELISA, by immunohistochemistry with anti-A␤ antibody, it was evidently shown that the administration of nobiletin decreased the A␤ burden and plaques in the hippocampus of APP-SL 7-5 Tg mice. These findings suggest that this natural compound has potential to become a novel drug for fundamental treatment of AD.

The polymorphism at codon 219 of the prion protein gene (PRNP) was found in the general Japanese population with 6% allele frequency. Herein, we examined 85 cases of sporadic Creutzfeldt-Jakob disease (CJD) for the codon 219 polymorphism. The codon 219Glu/Lys heterozygous polymorphism was not found in these CJD cases. In addition, we examined 43 patients with dementia of non-CJD origin, and 4 were found to have the codon 219Glu/Lys heterozygous polymorphism with a similar allele frequency as in the general population. Thus, the codon 219Glu/Lys heterozygous polymorphism might be uniquely excluded from sporadic CJD.