Alzheimer Disease: Weksler ME

Szabo P, Relkin N, Weksler ME. · Department of Neurology, Weill Medical College of Cornell University, New York, NY 10021, USA. · Autoimmun Rev. · Pubmed #18558354 No free full text.

Abstract: Properties of human, natural anti-Abeta antibodies and commercially available intravenous immunoglobulin (IVIg) have been examined in light of the beneficial effects of passive immunotherapy with IVIg for patients with mild to moderate Alzheimer's disease (AD). Anti-Abeta antibodies in IVIg recognize conformation-specific epitopes as well as linear epitopes from different regions of the Abeta peptide. Anti-Abeta antibodies in circulation, especially those with high avidity, are often masked by ligands and the avidity of these antibodies increases upon dissociation of the bound ligands from the antibodies. Such natural anti-Abeta antibodies have the capacity to prevent Abeta oligomer-induced neurotoxicity in N2A neuroblastoma cells. This neuro-protective effect may reflect the therapeutic potential of the natural anti-Abeta antibodies found in IVIg for the treatment of patients with AD.

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.

Weksler ME, Gouras G, Relkin NR, Szabo P. · Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA. · Immunol Rev. · Pubmed #15882358 No free full text.

Abstract: In this review, the case is made that amyloid-beta peptide in the brain of patients with Alzheimer's disease is a primary cause of the disease and that immunotherapy directed against this peptide has the potential to halt and/or reverse disease progression. This supposition is supported by the capacity of anti-beta-amyloid peptide antibodies to prevent or reverse the disease in mouse models of Alzheimer's disease. Furthermore, preliminary results obtained in a small number of patients with Alzheimer's disease are consistent with the observations made in the mouse model of this disease. We review the relationship between the immune system, amyloid-beta peptide, and Alzheimer's disease and the progress made in applying immunotherapy to patients with Alzheimer's disease.

Weksler ME, Goodhardt M. · Institut Pasteur, 34 rue du Docteur Roux, Paris 75015, France. · Exp Gerontol. · Pubmed #12213547 No free full text.

Abstract: More than 25 years ago, Pierre Grabar proposed that the age-associated increase in serum autoantibodies reflected a homeostatic function of the immune system that defended the internal milieu by targeting senescent molecules and cells for elimination. This mini-review examines recent evidence that autoantibodies may influence the risk of the elderly developing infectious, atherosclerotic, or Alzheimer's disease. Auto-anti-idiotypic antibodies suppress the antibody response to the nominal antigen and, thus, may contribute to the increased risk of infection and poor response to vaccines in the elderly. In contrast, low levels of autoantibodies to oxidised low-density lipoproteins or to the amyloid beta peptide may contribute to the increased risk of developing atherosclerosis of Alzheimer's disease, respectively.

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.

Weksler ME, Relkin N, Turkenich R, LaRusse S, Zhou L, Szabo P. · Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA. · Exp Gerontol. · Pubmed #12086704 No free full text.

Abstract: Active immunization with the human amyloid peptide (Abeta42) or passive immunization with anti-Abeta42 antibodies protects mice that express a mutant human amyloid precursor protein (APP) transgene from cerebral amyloid deposits. If anti-Abeta42 antibodies protect APP-transgenic mice, a model of Alzheimer's disease (AD), a high titer of anti-Abeta42 antibodies may protect humans from AD. The titer of anti-Abeta42 antibodies in serum from individuals with and without late onset AD was measured using an ELISA. The titer of Ig (IgM, IgG and IgA) and IgG anti-Abeta42 peptide antibodies was significantly higher in serum from elderly controls than AD patients. Furthermore, IgG but not Ig anti-Abeta42 antibodies distinguished sera from AD patients and elderly controls that did not have the apolipoprotein E4 allele. The low titer of anti-Abeta42 antibodies in AD patients does not reflect the well-established, age-associated defect in the antibody response to most protein antigens, as there was no positive correlation between the serum titer of anti-Abeta42 antibodies and anti-influenza hemagglutinin antibodies induced by influenza vaccine in elderly humans. The lower titer of serum anti-Abeta42 peptide antibodies in AD patients may reflect the reported specific impairment of helper T cell activity for B cells that produce anti-amyloid-beta42 peptide antibodies in APP-transgenic mice.

D'Esposito M, Weksler ME. · University of California, Berkeley, USA. · Geriatrics. · Pubmed #10872346 No free full text.

Abstract: Geriatrics is pleased to highlight the clinical implications of research topics supported by the American Federation for Aging Research (AFAR). AFAR is a leading private organization supporting research on the aging process and diseases of older populations. More than 900 physicians, scientists, and students have received AFAR grants totaling more than $20 million since AFAR was founded by Irving S. Wright, MD, in 1981. The articles in the New Frontiers series are designed to provide primary care physicians with insight into the pathogenesis, diagnosis, prevention, and treatment of the diseases of aging.