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Atopic dermatitis (AD) is a common inflammatory skin disease of unknown etiology. Cutaneous infection with microbes such asMajor features of AD are pruritus, chronic relapsing course, and genetic predisposition (1-3). AD is divided into two types: (i) AD associated with IgE-mediated responses, affecting 70-80% of patients and termed ''extrinsic AD,'' and (ii) AD without IgEmediated responses, affecting 20-30% of patients and termed ''intrinsic AD.'' Patients with extrinsic AD show preferential deviation toward T helper type 2 (Th2) responses, together with accumulation of Th2 chemokines such as CCL17 (thymus-and activation-regulated chemokine) and CCL22 (monocyte-derived chemokine) in the cutaneous lesions (1, 2). However, recent clinical studies have revealed that the immunological aspects of the skin lesions are quite different among the clinical stages of AD (1-3). Nonetheless, the immunopathological bases for intrinsic AD are still unknown.Recently, we showed that transgenic mice that oversecrete IL-18 from their epidermal cells spontaneously develop AD-like dermatitis under specific pathogen-free (SPF) conditions, and that the deletion of il18, but not stat6, which encodes a signaling molecule necessary for Th2 and IgE responses, protects against the development of AD (4, 5). This finding suggests that excessive cutaneous IL-18 release is a causative factor for intrinsic-type AD. Recent clinical studies have revealed that IL-18 production levels closely parallel disease severity (6-8). Therefore, it is important to clarify whether, and how, endogenous IL-18 contributes to the development of AD when skin is exposed to natural infectious agents.Although it is well documented that cutaneous infection with Staphylococcus aureus exacerbates clinical AD (1, 3), the underlying mechanism is not fully understood. Recently, we demonstrated that protein A (SpA), a surface molecule and virulent factor of S. aureus (9), stimulates mouse epidermal cells to secrete IL-18 (10). However, cutaneous application of SpA alone did not induce major skin alterations in C57BL͞6 mice, despite the fact that it produced elevated serum levels of 10). This outcome led us to assume that additional factors are required for the development of AD. Because skin cleansing with detergent aggravates clinical AD (1, 11), skin barrier destruction seems to be a second important factor in AD development. Inasmuch as NC͞Nga mice, which have a genetically impaired skin barrier due to reduced ceramide production (12), frequently develop AD-like dermatitis after exposure to mites (13-15), we assumed that genetic skin barrier dysfunction was a third prerequisite for the development of AD. Here, we generated an intrinsic AD mouse model by daily application of SpA, after destruction of the skin barrier with a subclinical dose of SDS, a detergent (16). Neutralizing anti-IL-18 Abs could completely protect against SDS͞SpA-induced AD. Furthermore, il18 Ϫ/Ϫ BALB͞c mice evaded development of AD under SDS͞SpA challenge. Our present results clearly demonstrate th...

Increasing evidence suggests that α-synuclein (αS) aggregates in brains of individuals with Parkinson's disease and dementia with Lewy bodies can spread in a prion-like manner. Although the initial αS nuclei are pivotal in determining αS fibril polymorphs and resulting phenotypes, it is not clear how the initial fibril seeds are generated. Previous studies have shown that αS truncation might have an important role in αS aggregation. However, little is known about how this truncation influences αS's propagation properties. In the present study, we generated αS fibrils from a series of truncated human αS constructs, characterized their structures and conformational stabilities, and investigated their ability to convert the conformation of full-length αS , in cultured cells, and in WT mice. We show that both C- and N-terminal truncations of human αS induce fibril polymorphs and exhibit different cross-seeding activities. N-terminally 10- or 30-residue-truncated human αS fibrils induced more abundant αS pathologies than WT fibrils in mice, whereas other truncated fibrils induced less abundant pathologies. Biochemical analyses of these truncated fibrils revealed that N-terminal 10- or 30-residue truncations of human αS change the fibril conformation in a manner that increases their structural compatibility with WT mouse αS fibrils and reduces their stability. C-terminally 20-residue-truncated fibrils displayed enhanced seeding activity Our findings imply that truncation of αS can influence its prion-like pathogenicity, resulting in phenotypic diversity of α-synucleinopathies.

In patients with hepatic cirrhosis, the globus pallidus and putamen show high intensity on T1-weighted MRI. While the causes of this high signal have been thought to include paramagnetic substances, especially manganese, no evidence for this has been presented. Autopsy in four cases of hepatic cirrhosis permitted measurement of metal concentrations in brain and histopathological examination. In three cases the globus pallidus showed high intensity on T1-weighted images. Mean manganese concentrations in globus pallidus, putamen and frontal white matter were 3.03 +/- 0.38, 2.12 +/- 0.37, and 1.38 +/- 0.24 (micrograms/g wet weight), respectively, being approximately four- to almost ten-fold the normal values. Copper concentrations in globus pallidus and putamen were also high, 50% more than normal. Calcium, iron, zinc and magnesium concentrations were all normal. The fourth case showed no abnormal intensity in the basal ganglia and brain metal concentrations were all normal. Histopathologically, cases with showing high signal remarkable atrophy, necrosis, and deciduation of nerve cells and proliferation of glial cells and microglia in globus pallidus.. These findings were similar to those in chronic manganese poisoning. On T1-weighted images, copper deposition shows no abnormal intensity. It is therefore inferred that deposition of highly concentrations of manganese may caused high signal on T1-weighted images and nerve cell death in the globus pallidus.

Metastin/kisspeptin, a hypothalamic peptide, plays a pivotal role in controlling GnRH neurons. Here we studied the effect of chronic sc administration of two kisspeptin analogs, KISS1-305 and TAK-448, on hypothalamic-pituitary-gonadal function in male rats in comparison with a GnRH analogue leuprolide or bilateral orchiectomy (ORX). The prototype polypeptide, KISS1-305 (1-4 nmol/h), caused substantial elevations of plasma LH and testosterone, followed by abrupt reductions of both hormone levels. Notably, testosterone levels were reduced to castrate levels within 3 d and remained depleted throughout the 4-wk dosing period, an effect that was faster and more pronounced than leuprolide (1 nmol/h) dosing. KISS1-305 also reduced genital organ weight more profoundly than leuprolide. In mechanistic studies, chronic KISS1-305 administration only transiently induced c-Fos expression in GnRH neurons, suggesting that GnRH-neural response was attenuated over time. Hypothalamic GnRH content was reduced to 10-20% of control at 3 wk without any changes in Gnrh mRNA expression. Dosing with the investigational peptide TAK-448 was also studied to extend our understanding of hypothalamic-pituitary functions. Similar to ORX, TAK-448 (0.1 nmol/h) depleted testosterone and decreased GnRH content by 4 wk. However, in contrast to ORX, TAK-448 decreased gonadotropin levels in pituitary and plasma samples, implying the suppression of GnRH pulses. These results suggest that chronic administration of kisspeptin analogs disrupts endogenous kisspeptin signals to suppress intrinsic GnRH pulses, perhaps by attenuating GnRH-neural response and inducing continuous GnRH leakage from the hypothalamus. The potential utility of kisspeptin analogs as novel agents to treat hormone-related diseases, including prostate cancer, is discussed.

␣-Synuclein is the major component of Lewy bodies and Lewy neurites in Parkinson disease and dementia with Lewy bodies and of glial cytoplasmic inclusions in multiple system atrophy. It has been suggested that ␣-synuclein fibrils or intermediate protofibrils in the process of fibril formation may have a toxic effect on neuronal cells. In this study, we investigated the ability of soluble monomeric ␣-synuclein to promote microtubule assembly and the effects of conformational changes of ␣-synuclein on Tau-promoted microtubule assembly. In marked contrast to previous findings, monomeric ␣-synuclein had no effect on microtubule polymerization. However, both ␣-synuclein fibrils and protofibrils inhibited Tau-promoted microtubule assembly. The inhibitory effect of ␣-synuclein fibrils was greater than that of the protofibrils. Dot blot overlay assay and spin-down techniques revealed that ␣-synuclein fibrils bind to Tau and inhibit microtubule assembly by depleting the Tau available for microtubule polymerization. Using various deletion mutants of ␣-synuclein and Tau, the acidic C-terminal region of ␣-synuclein and the basic central region of Tau were identified as regions involved in the binding. Furthermore, introduction of ␣-synuclein fibrils into cultured cells overexpressing Tau protein induced Tau aggregation. These results raise the possibility that ␣-synuclein fibrils interact with Tau, inhibit its function to stabilize microtubules, and also promote Tau aggregation, leading to dysfunction of neuronal cells.

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