Inhibition of amyloid- (A) aggregation is an attractive therapeutic strategy for Alzheimer's disease (AD). Certain phenolic compounds have been reported to have anti-A aggregation effects in vitro.This study systematically investigated the effects of phenolic compounds on AD model transgenic mice (Tg2576). Mice were fed five phenolic compounds (curcumin, ferulic acid, myricetin, nordihydroguaiaretic acid (NDGA), and rosmarinic acid (RA)) for 10 months from the age of 5 months. Immunohistochemically, in both the NDGA-and RA-treated groups, A deposition was significantly decreased in the brain (P < 0.05). In the RA-treated group , the level of Trisbuffered saline (TBS)-soluble A monomers was increased (P < 0.01), whereas that of oligomers, as probed with the A11 antibody (A11-positive oligomers), was decreased (P < 0.001). However, in the NDGA-treated group, the abundance of A11-positive oligomers was increased (P < 0.05) without any change in the levels of TBS-soluble or TBS-insoluble A. In the curcumin-and myricetin-treated groups, changes in the A profile were similar to those in the RA-treated group, but A plaque deposition was not significantly decreased. In the ferulic acid-treated group, there was no significant difference in the A profile. These results showed that oral administration of phenolic compounds prevented the development of AD pathology by affecting different A aggregation pathways in vivo. Clinical trials with these compounds are necessary to confirm the anti-AD effects and safety in humans. Alzheimer's disease (AD) is the most common form of dementia, resulting in deterioration of cognitive function and behavioral changes.1 One of the pathological hallmarks of AD is extracellular deposits of aggregated amyloid- protein (A) in the brain parenchyma (senile plaques) and cerebral blood vessels (cerebral amyloid angiopathy (CAA)).1 Deposition of high levels of fibrillar A in the AD brain is associated with loss of synapses, impairment of neuronal functions, and loss of neurons. 2-5A was sequenced from meningeal vessels and senile plaques of AD patients and individuals with Down's syndrome.6 -8 The subsequent cloning of the gene encoding the -amyloid precursor protein and its localization to chromosome 21, 9 -12 coupled with the earlier recognition that trisomy 21 (Down's syndrome) invariably leads to the neuropathology of AD, 13 set the stage for the proposal that A accumulation is the primary event in AD pathogenesis. In addition, certain mutations associated with familial AD have been identified within or near the A region of the coding sequence of gene of the amyloid precursor proteins, 14,15 presenilin-1 and presenilin-2, 16 which alter amyloid precursor protein metabolism through a direct effect on ␥-secretase. 17,18 These findings set the stage for the proposal that A aggregation is the primary event in AD pathogenesis and leading to the proposal that anti-A aggregation is a strategy for AD therapy.
Appropriate resources and expression technology necessary for human proteomics on a whole-proteome scale are being developed. We prepared a foundation for simple and efficient production of human proteins using the versatile Gateway vector system. We generated 33,275 human Gateway entry clones for protein synthesis, developed mRNA expression protocols for them and improved the wheat germ cell-free protein synthesis system. We applied this protein expression system to the in vitro expression of 13,364 human proteins and assessed their biological activity in two functional categories. Of the 75 tested phosphatases, 58 (77%) showed biological activity. Several cytokines containing disulfide bonds were produced in an active form in a nonreducing wheat germ cell-free expression system. We also manufactured protein microarrays by direct printing of unpurified in vitro-synthesized proteins and demonstrated their utility. Our 'human protein factory' infrastructure includes the resources and expression technology for in vitro proteome research.
Keratan sulfate (KS) is a glycosaminoglycan composed of repeating disaccharide units with sulfate residues at the C6 positions of galactose and N-acetylglucosamine (GlcNAc). The N-acetylglucosamine 6-O-sulfotransferase(s) (GlcNAc6ST) involved in the synthesis of KS in the central nervous system (CNS) has long been unidentified. Here, we report that a deficiency of GlcNAc6ST-1 leads to loss of 5D4-reactive brain KS and reduction of glial scar formation after cortical stab injury in mice. During the development of mice deficient in GlcNAc6ST-1, KS expression in the brain was barely detectable with the KS-specific antibody 5D4. The reactivity of 5D4 antibody with protein tyrosine phosphatase zeta (PTPzeta), a KS proteoglycan (KSPG), was abolished in the deficient mice. In adults, brain injury induced 5D4-reactive KS synthesis in the wounded area in wild-type (WT) mice but not in the deficient mice. Glial scar is formed via the accumulation of reactive astrocytes and is a major obstacle to axonal regeneration by injured neurons. Reactive astrocytes appeared to similar extents in the two genotypes, but they accumulated in the wounded area to a lesser extent in the deficient mice. Consequently, the deficient mice exhibited a marked reduction of scarring and enhanced neuronal regeneration after brain injury. These findings highlight the indispensable role of GlcNAc6ST-1 in brain KS biosynthesis and glial scar formation after brain injury.
Pulmonary alveolar proteinosis (PAP) is classified as autoimmune, secondary, or genetic. We herein describe a 69-year-old man with autoimmune PAP, simultaneously diagnosed with myeloproliferative neoplasm (MPN). Two years after the diagnosis, the MPN progressed to acute myeloid leukemia, and the patient died from an alveolar hemorrhage during remission induction chemotherapy. Throughout the clinical course, no progression of PAP was observed, despite the progression to leukemia. There are few reports of autoimmune PAP with hematological malignancy, and this case demonstrated that an evaluation for GM-CSF autoantibodies is important for distinguishing the autoimmune and secondary forms of PAP, even if the patient has hematological malignancy.
Though adult-onset primary autoimmune pancytopenia (AIP) rarely follows a self-limited course, a standard treatment strategy has not yet been established. We herein report two cases, each involving primary autoimmune neutropenia complicated with autoimmune thrombocytopenia or Evans syndrome. They were refractory to granulocyte-colony stimulating factor, but all lineages of cytopenia promptly recovered with prednisolone (PSL). In case 1, PSL was tapered and discontinued six months after its initiation without AIP relapse. In case 2, PSL has been tapered for five months without relapse. To establish an optimal treatment strategy for AIP, it is necessary to accumulate more cases.
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