Airway hyperreactivity (AHR), eosinophilic inflammation with a Th2-type cytokine profile, and specific Th2-mediated IgE production characterize allergic asthma. In this paper, we show that OVA-immunized Jα18−/− mice, which are exclusively deficient in the invariant Vα14+ (iVα14), CD1d-restricted NKT cells, exhibit impaired AHR and airway eosinophilia, decreased IL-4 and IL-5 production in bronchoalveolar lavage fluid, and reduced OVA-specific IgE compared with wild-type (WT) littermates. Adoptive transfer of WT iVα14 NKT cells fully reconstitutes the capacity of Jα18−/− mice to develop allergic asthma. Also, specific tetramer staining shows that OVA-immunized WT mice have activated (CD69+) iVα14 NKT cells. Importantly, anti-CD1d mAb treatment blocked the ability of iVα14 T cells to amplify eosinophil recruitment to airways, and both Th2 cytokine and IgE production following OVA challenge. In conclusion, these findings clearly demonstrate that iVα14 NKT cells are required to participate in allergen-induced Th2 airway inflammation through a CD1d-dependent mechanism.

Objective: Recently, the importance of non-pharmacological therapies for dementia has come to the fore. In the present study, we examined the curative effects of aromatherpay in dementia in 28 elderly people, 17 of whom had Alzheimer's disease (AD). Methods: After a control period of 28 days, aromatherapy was performed over the following 28 days, with a wash out period of another 28 days. Aromatherapy consisted of the use of rosemary and lemon essential oils in the morning, and lavender and orange in the evening. To determine the effects of aromatherpay, patients were evaluated using the Japanese version of the Gottfries, Brane, Steen scale (GBSS-J), Functional Assessment Staging of Alzheimer's disease (FAST), a revised version of Hasegawa's Dementia Scale (HDS-R), and the Touch Panel-type Dementia Assessment Scale (TDAS) four times: before the control period, after the control period, after aromatherpay, and after the washout period. Results: All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit's score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests. Conclusions:In conclusion, we found aromatherapy an efficacious nonpharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients.

Invariant NKT (inv. NKT) cells co-express an invariant § g T cell receptor and the NK receptor NK1.1 and, upon CD1d-restricted recognition of the glycosphingolipid antigen § -galactosyl ceramide ( § GalCer), secrete large amounts of regulatory cytokines. We investigated whether § GalCer-dependent activation of inv. NKT cells protects from experimental autoimmune encephalomyelitis (EAE), an immune-mediated disease of the central nervous system mimicking multiple sclerosis, induced in C57BL/6 mice by the myelin oligodendrocyte glycoprotein (MOG) encephalitogenic peptide aa 35-55. § GalCer was administered at the time of immunization s.c., mixed with complete Freund's adjuvant and MOG35-55 peptide, or administered i.p., diluted in PBS. EAE onset was delayed and disease severity was decreased only when § GalCer was s.c. administered. The protective effect of s.c. administration of § GalCer was associated with a markedly enhanced IFN-+ production by liverconfined inv. NKT cells which, in turn, suppressed Th1-cytokine production and fostered secretion of IL-10 from MOG35-55-specific T cells. In vivo neutralization of IFN-+ , but not IL-4, reversed the protective effect induced by s.c. administration of § GalCer, further confirming the critical regulatory role exerted by IFN-+ -producing inv. NKT cells. Our results indicate that § GalCer, properly administered, may elicit an inv. NKT-cell-mediated suppressive effect on the effector function of encephalitogenic T cells; this effect is able to ameliorate autoimmune demyelination.

Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins, designated Alc ␣ , Alc ␤ , and Alc ␥ . The Alcs express in neurons dominantly and largely colocalize with the Alzheimer amyloid precursor protein (APP) in the brain. Alcs and APP show an identical function as a cargo receptor of kinesin-1. Moreover, proteolytic processing of Alc proteins appears highly similar to that of APP. We found that APP ␣-secretases ADAM 10 and ADAM 17 primarily cleave Alc proteins and trigger the subsequent secondary intramembranous cleavage of Alc C-terminal fragments by a presenilin-dependent ␥-secretase complex, thereby generating "APP p3-like" and non-aggregative Alc peptides (p3-Alcs). We determined the complete amino acid sequence of p3-Alc ␣ , p3-Alc ␤ , and p3-Alc ␥ , whose major species comprise 35, 37, and 31 amino acids, respectively, in human cerebrospinal fluid. We demonstrate here that variant p3-Alc C termini are modulated by FAD-linked presenilin 1 mutations increasing minor ␤-amyloid species A␤42, and these mutations alter the level of minor p3-Alc species. However, the magnitudes of C-terminal alteration of p3-Alc ␣ , p3-Alc ␤ , and p3-Alc ␥ were not equivalent, suggesting that one type of ␥-secretase dysfunction does not appear in the phenotype equivalently in the cleavage of type I membrane proteins. Because these C-terminal alterations are detectable in human cerebrospinal fluid, the use of a substrate panel, including Alcs and APP, may be effective to detect ␥-secretase dysfunction in the prepathogenic state of Alzheimer disease subjects. Alcadein (Alc)5 proteins comprise a family of evolutionarily conserved, type I membrane proteins that are predominantly expressed in neuronal tissues. Alc has been independently identified as a binding protein for the neuron-specific adaptor protein X11L (X11-like) (1) and as a postsynaptic Ca 2ϩ -binding protein, where it is known by the name calsyntenin (2). Alc functions as a cargo-receptor for the kinesin-1 motor that mediates anterograde transport of APP (3, 4), and a mutation in a nematode ortholog of the Alc gene is reported to cause a defect in associative learning (5, 6). Thus, Alc plays important roles in vesicular transport at the subcellular level and in learning behavior at the organismal level. Alc exists as four isoforms in mammals: Alc ␣1 (971 amino acids in humans), Alc ␣2 (981 amino acids in humans), Alc ␤ (956 amino acids in humans), and Alc ␥ (955 amino acids in humans) (1). Alc ␣ , Alc ␤ , and Alc ␥ are * This work was supported, in whole or in part, by National Institutes of Health, NIA, Grants R01 AG23611, P01 AG10491, and P50 AG005138 (to S. G.). This work was also supported in part by Grants-in-aid for Scientific Research on Priority Areas 20023001 (to T. S.) from the Ministry of Education, Science, Culture, Sports, and Technology, Japan. □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental

CSF Aβ1-42 discriminates AD dementia from FTD, but shows significant overlap with other non-AD forms of dementia, possibly reflecting the underlying mixed pathologies.