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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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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.

The neuronal cytoskeleton is one of the most profoundly altered organelles in late life neuro-degenerative disorders that are characterized by progressive impairments in cognitive abilities. The elucidation of the protein building blocks of these organelles as well as advances in understanding how these proteins become altered in Alzheimer's disease (AD) and other less common dementing illnesses, i.e., diffuse Lewy body disease (DLBD) or the Lewy body variant of AD (LBVAD), will provide insights into the molecular basis of these disorders. Within, we review evidence that normal adult human tau is abnormally phosphorylated and converted into the subunits of AD paired helical filaments (PHFs), and that Lewy bodies (LBs) represent accumulation of altered neurofilament (NF) triplet subunits. Although the precise biological consequences of PHF and LB formation in neurons is unknown, growing evidence suggests that the formation of PHFs and LBs from normal neuronal cytoskeletal proteins could have deleterious effects on neuronal function and survival. Finally, insights into the composition of PHFs and LBs could lead to the development of novel strategies for the timely and accurate diagnosis of AD, DLBD and the LBVAD.

The peptidyl prolyl cis/trans isomerase Pin1 specifically binds phosphorylated Ser/Thr-Pro protein motifs and catalyzes the cis/trans isomerization of the peptide bond. Accumulating studies have revealed that Pin1 isomerase activity is regulated by its post-translational modifications, including phosphorylation and oxidation. Various transcription factors and regulators have been identified as substrates for Pin1. It enhances AP-1 activity via isomerization of both c-Jun and c-Fos for cellular proliferation and stabilizes the oncosuppressors p53 and p73 against DNA damage at the checkpoint. We demonstrated the association between the intracellular form of Notch1 (NIC) and Pin1 by analyzing Pin1/p53 double-knockout mice. Pin1 also regulates the post-transcriptional level of some cytokines, associated with asthma, that possess 3' untranslated region AU-rich elements (AREs) via interaction withAUF1, the nucleoprotein in the ARE-binding complex. Pin1 has been identified as the molecular partner of tau and amyloid precursor protein (APP), the key factors of Alzheimer's disease (AD). It interacts with the phosphorylated Thr-231 of tau and regulates its activity to bind microtubules. It further interacts with the phosphorylated Thr-668 of APP and affects its metabolism. Thus, Pin1 is probably involved in the pathogenesis of human diseases, including cancer, asthma, and AD, presenting an attractive target for future therapeutical drugs.

Niemann-Pick Type C disease (NPC) is a cholesterol storage disease with defects in the intracellular trafficking of exogenous cholesterol derived from low density lipoproteins. In NPC cases with a chronic progressive course, neurofibrillary tangles (NFTs) that consist of paired helical filaments (PHFs) have been reported. To determine if NPC tangles contain abnormal tau proteins (known as PHFtau) similar to those found in Alzheimer's disease (AD) tangles, we examined the brains of five NPC cases by immunohistochemical and Western blot methods using a library of antibodies to defined epitopes of PHFtau. We show here that PHFtau in tangle-rich NPC brains is indistinguishable from PHFtau in AD brains. We speculate, that the generation of PHFtau in NPC may induce a cascade of pathological events that contribute to the widespread degeneration of neurons, and that these events may be similar in NPC and AD.