Alzheimer Disease: Planque S

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.

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.

Rangan SK, Liu R, Brune D, Planque S, Paul S, Sierks MR. · Department of Chemical and Materials Engineering, Arizona State University, Tempe, Arizona 85287, USA. · Biochemistry. · Pubmed #14640701 No free full text.

Abstract: Deposition of beta-amyloid (Abeta) is considered an important early event in the pathogenesis of Alzheimer's disease (AD). Clearance of Abeta thus represents a potential therapeutic approach. Antibody-mediated clearance of Abeta by vaccination inhibited and cleared Abeta deposition in animal models; however, inflammatory side effects were observed in humans. An alternative potentially noninflammatory approach to facilitate clearance is to proteolytically cleave Abeta. We screened 12 proteolytic recombinant antibody fragments for potential alpha-secretase activity, a naturally occurring enzyme that cleaves between the Lys16 and Leu17 residues of the amyloid precursor protein (APP). We utilized the synthetic alpha-secretase substrate, benzyloxycarbonyl-l-lysine o-nitrophenyl ester (Z-lys-o-Np) as a preliminary screen for alpha-secretase activity. Two antibody light chain fragments that hydrolyzed Z-lys-o-Np were identified. Abeta hydrolysis was studied using mass spectrometry to identify the cleavage patterns of the antibodies. The recombinant antibody light chain antibody fragment, c23.5, showed alpha-secretase-like activity, producing the 1-16 and 17-40 amino acid fragments of Abeta. The second light chain antibody fragment, hk14, demonstrated carboxypeptidase-like activity, cleaving sequentially from the carboxyl terminal of Abeta. These antibody light chains provide a novel route toward engineering efficient therapeutic antibodies capable of cleaving Abeta in vivo.