Alzheimer Disease: Nishiyama Y

Taguchi H, Planque S, Nishiyama Y, Szabo P, Weksler ME, Friedland RP, Paul S. · Chemical Immunology Research Center, University of Texas Houston Medical School, Houston, TX 77030, USA. · Autoimmun Rev. · Pubmed #18486927 links to  free full text

Abstract: Immunoglobulins (Igs) that bind amyloid beta peptide (Abeta) are under clinical trials for immunotherapy of Alzheimer disease (AD). We have identified IgMs and recombinant Ig fragments that hydrolyze Abeta. Hydrolysis of peripheral Abeta by the IgMs may induce increased Abeta release from the brain. The catalytic IgMs are increased in AD patients, presumably reflecting a protective autoimmune response. Reduced Abeta aggregation and neurotoxicity attributable to the catalytic function were evident. These findings provide a foundation for development of catalytic Igs for AD immunotherapy.

Hanson CV, Nishiyama Y, Paul S. · Viral and Rickettsial Disease Laboratory, California Department of Health Services, Richmond, 94804, USA. · Curr Opin Biotechnol. · Pubmed #16243512 No free full text.

Abstract: Catalytic antibodies (CAbs) occur naturally in healthy individuals where they may form part of the innate immune system, but are preferentially found in those with autoimmune disease. CAbs can also be artificially engineered or elicited by immunizations. Their mechanisms of action include nucleophilic catalysis, induction of conformational strain, coordination with metal ions, and stabilization of transition states. Recent applications of CAbs with clinical significance include the conversion of cocaine to a non-psychoactive form, the degradation of nicotine, activation of prodrugs for targeted chemotherapy, protection from ultraviolet radiation, inhibition of HIV infectivity, and the destruction of aggregates of beta-amyloid implicated in Alzheimer's disease. Artificial CAbs are likely to find increasing applications in research, clinical medicine, diagnostics and manufacturing.

Taguchi H, Planque S, Sapparapu G, Boivin S, Hara M, Nishiyama Y, Paul S. · Chemical Immunology Research Center, Department of Pathology and Laboratory Medicine, University of Texas Houston Medical School, Houston, Texas 77030, USA. · J Biol Chem. · Pubmed #18974093 No free full text.

Abstract: Nucleophilic sites in the paired variable domains of the light and heavy chains (VL and VH domains) of Ig can catalyze peptide bond hydrolysis. Amyloid beta (Abeta)-binding Igs are under consideration for immunotherapy of Alzheimer disease. We searched for Abeta-hydrolyzing human IgV domains (IgVs) in a library containing a majority of single chain Fv clones mimicking physiological VL-VH-combining sites and minority IgV populations with nonphysiological structures generated by cloning errors. Random screening and covalent selection of phage-displayed IgVs with an electrophilic Abeta analog identified rare IgVs that hydrolyzed Abeta mainly at His14-Gln15. Inhibition of IgV catalysis and irreversible binding by an electrophilic hapten suggested a nucleophilic catalytic mechanism. Structural analysis indicated that the catalytic IgVs are nonphysiological structures, a two domain heterodimeric VL (IgVL2-t) and single domain VL clones with aberrant polypeptide tags (IgVL-t'). The IgVs hydrolyzed Abeta at rates superior to naturally occurring Igs by 3-4 orders of magnitude. Forced pairing of the single domain VL with VH or VL domains resulted in reduced Abeta hydrolysis, suggesting catalysis by the unpaired VL domain.Angstrom level amino acid displacements evident in molecular models of the two domain and unpaired VL domain clones explain alterations of catalytic activity. In view of their superior catalytic activity, the VL domain IgVs may help attain clearance of medically important antigens more efficiently than natural Igs.

Taguchi H, Planque S, Nishiyama Y, Symersky J, Boivin S, Szabo P, Friedland RP, Ramsland PA, Edmundson AB, Weksler ME, Paul S. · Chemical Immunology Research Center, Department of Pathology and Laboratory Medicine, University of Texas Houston Medical School, Houston, Texas 77030, USA. · J Biol Chem. · Pubmed #18086674 links to  free full text

Abstract: We describe IgM class human autoantibodies that hydrolyze amyloid beta peptide 1-40 (Abeta40). A monoclonal IgM from a patient with Waldenström's macroglobulinemia hydrolyzed Abeta40 at the Lys-28-Gly-29 bond and Lys-16-Ala-17 bonds. The catalytic activity was inhibited stoichiometrically by an electrophilic serine protease inhibitor. Treatment with the catalytic IgM blocked the aggregation and toxicity of Abeta40 in neuronal cell cultures. IgMs purified from the sera of patients with Alzheimer disease (AD) hydrolyzed Abeta40 at rates superior to IgMs from age-matched humans without dementia. IgMs from non-elderly humans expressed the least catalytic activity. The reaction rate was sufficient to afford appreciable degradation at physiological Abeta and IgM concentrations found in peripheral circulation. Increased Abeta concentrations in the AD brain are thought to induce neurodegenerative effects. Peripheral administration of Abeta binding antibodies has been suggested as a potential treatment of AD. Our results suggest that catalytic IgM autoantibodies can help clear Abeta, and they open the possibility of using catalytic Abs for AD immunotherapy.

Mori I, Kimura Y, Naiki H, Matsubara R, Takeuchi T, Yokochi T, Nishiyama Y. · Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Aichi, Japan. · J Med Virol. · Pubmed #15221907 No free full text.

Abstract: Herpes simplex virus type 1 (HSV-1) has been proposed as an environmental risk factor for sporadic Alzheimer's disease, although this issue is still in dispute. The involvement of HSV-1 in the pathogenesis of familial Alzheimer's disease, the uncommon type of Alzheimer's disease, has not been addressed yet. We investigated formalin-fixed, paraffin-embedded, postmortem brain tissue sections of three patients with familial Alzheimer's disease for the presence of HSV-1 DNA. The nested polymerase chain reaction (PCR) detected the HSV-1 glycoprotein D gene in the brain of all three patients with familial Alzheimer's disease preferentially in the frontal and temporal cortices, whereas only one case out of six age-matched, non-Alzheimer's disease individuals could disclose the presence of HSV-1 gene. The PCR detected HSV-1 DNA in the frontal cortex of the two patients with sporadic Alzheimer's disease. The presence of HSV-1 was associated with beta-amyloid deposition in the cerebral cortex. To clarify the localization of HSV-1 in the brain tissue of patients with familial Alzheimer's disease, the in situ hybridization of the tyramide signal amplification system was used. It detected the HSV-1-specific signals predominantly in the cytoplasm of cortical neurons in a dot-like staining fashion. In addition, high-sensitivity immunohistochemistry revealed the existence of HSV-1 antigens in the cytoplasm of cortical neurons. This report provides the first evidence of reactivation of HSV-1 in the brain of patients with familial Alzheimer's disease, associated with beta-amyloid deposition, and suggests the possible involvement of HSV-1 together with genetic factors in the pathogenesis of familial Alzheimer's disease.

Mori I, Yokochi T, Koide N, Sugiyama T, Yoshida T, Kimura Y, Naiki H, Matsubara R, Takeuchi T, Nishiyama Y. · No affiliation provided · J Clin Microbiol. · Pubmed #14766896 links to  free full text

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