Catalytic antibodies to amyloid β peptide in defense against Alzheimer disease
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.
Full-textDOI: · Available from: Robert P Friedland, May 28, 2015
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ABSTRACT: To retrospectively determine the frequency of N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) autoantibodies in patients with different forms of dementia. Clinical characterization of 660 patients with dementia, neurodegenerative disease without dementia, other neurological disorders and age-matched healthy controls combined with retrospective analysis of serum or cerebrospinal fluid (CSF) for the presence of NMDAR antibodies. Antibody binding to receptor mutants and the effect of immunotherapy were determined in a subgroup of patients. Serum NMDAR antibodies of IgM, IgA, or IgG subtypes were detected in 16.1% of 286 dementia patients (9.5% IgM, 4.9% IgA, and 1.7% IgG) and in 2.8% of 217 cognitively healthy controls (1.9% IgM and 0.9% IgA). Antibodies were rarely found in CSF. The highest prevalence of serum antibodies was detected in patients with "unclassified dementia" followed by progressive supranuclear palsy, corticobasal syndrome, Parkinson's disease-related dementia, and primary progressive aphasia. Among the unclassified dementia group, 60% of 20 patients had NMDAR antibodies, accompanied by higher frequency of CSF abnormalities, and subacute or fluctuating disease progression. Immunotherapy in selected prospective cases resulted in clinical stabilization, loss of antibodies, and improvement of functional imaging parameters. Epitope mapping showed varied determinants in patients with NMDAR IgA-associated cognitive decline. Serum IgA/IgM NMDAR antibodies occur in a significant number of patients with dementia. Whether these antibodies result from or contribute to the neurodegenerative disorder remains unknown, but our findings reveal a subgroup of patients with high antibody levels who can potentially benefit from immunotherapy.
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ABSTRACT: Like infectious disease vaccines, effective Alzheimer's disease vaccines should elicit an antibody response similar to the natural autoantibodies found in serum and preparations of intravenous immunoglobulins, which recognize an array of amyloid-β conformations. An immune response that is the result of a progressive formation over time of antibodies against toxic amyloid-β conformations and that different from most vaccines under development, would require the whole protein as an antigen, including both B and T-cell epitopes. However, due to the presence of amyloid-β T-cell epitopes and the fact that such a protein is a Th1 immune modulator, safe and effective vaccines, besides eliciting Th2 immunity, should inhibit but not abolish Th1 immunity, which is needed for protection against pathogens; a strategy that would apply to other potential Alzheimer's disease vaccine antigens, e.g. tau. Due to immunosenescence, these vaccines would be more effective for preventive rather than therapeutic purposes, as younger individuals produce a better immune response. Recently developed novel adjuvants that most probably act at the dendritic cell level and that can deliver such a selective Th2 immune modulation while inhibiting Th1 immunity, would be crucial for the development of these proposed vaccines. protein, where the whole protein or some of its peptides with Th1 adjuvants may trigger a damaging inflammatory response [16,17]. Hence, there is a need to reassess the current AD vaccine paradigm and consider new approaches to its development. Different from infectious disease vaccines where the number of Th1 adjuvants is large, vaccines against neurodegenerative proteinopathies, like AD, have a negligible selection of adjuvants that stimulate solely Th2 immunity, alum being the most common . Still, that alum does not elicit an effective immunity in the elderly, as shown by the age-associated decrease in the efficacy of the flu and other vaccines  and have cumulative neurotoxicity , would preclude its use in AD vaccines. That certain bacterial toxins are "conditional" Th2 adjuvants, i.e. the stimulated immunity would depend on the age and mode of administration among other factors, adds an element of risk when used in large populations; for example, cholera toxin elicits Th2 immunity in young animals, but induces Th1 immunity in older ones , as well as a Th17 immune response . The recent reports that some well-defined helminth glycans and plant-derived glycosides elicit Th2-only immunity [18,23], despite the absence or presence of T-cell epitopes, offer a new approach to develop safe and effective AD vaccines. Access to adjuvants that stimulate Th2 but inhibit Th1 immunity would allow the use of whole proteins, e.g. Aβ 42 and tau; antigens that are not used because of the damaging inflammatory immune response caused by their T-cell epitopes. Significantly, since Aβ 42 has an intrinsic Th1 immune modulatory activity [24,25], the use of adjuvants that inhibit Th1 immunity will be essential with this antigen.
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ABSTRACT: Accumulation of amyloid beta-peptide (Aβ) in the brain is hypothesized to be a causal event leading to dementia in Alzheimer's disease (AD). Aβ vaccination removes Aβ deposits from the brain. Aβ immunotherapy, however, may cause T cell- and/or Fc-receptor-mediated brain inflammation and relocate parenchymal Aβ deposits to blood vessels leading to cerebral hemorrhages. Because catalytic antibodies do not form stable immune complexes and Aβ fragments produced by catalytic antibodies are less likely to form aggregates, Aβ-specific catalytic antibodies may have safer therapeutic profiles than reversibly-binding anti-Aβ antibodies. Additionally, catalytic antibodies may remove Aβ more efficiently than binding antibodies because a single catalytic antibody can hydrolyze thousands of Aβ molecules. We previously isolated Aβ-specific catalytic antibody, IgVL5D3, with strong Aβ-hydrolyzing activity. Here, we evaluated the prophylactic and therapeutic efficacy of brain-targeted IgVL5D3 gene delivery via recombinant adeno-associated virus serotype 9 (rAAV9) in an AD mouse model. One single injection of rAAV9-IgVL5D3 into the right ventricle of AD model mice yielded widespread, high expression of IgVL5D3 in the unilateral hemisphere. IgVL5D3 expression was readily detectable in the contralateral hemisphere but to a much lesser extent. IgVL5D3 expression was also confirmed in the cerebrospinal fluid. Prophylactic and therapeutic injection of rAAV9-IgVL5D3 reduced Aβ load in the ipsilateral hippocampus of AD model mice. No evidence of hemorrhages, increased vascular amyloid deposits, increased proinflammatory cytokines, or infiltrating T-cells in the brains was found in the experimental animals. AAV9-mediated anti-Aβ catalytic antibody brain delivery can be prophylactic and therapeutic options for AD.Molecular Neurobiology 04/2014; 51(1). DOI:10.1007/s12035-014-8691-z · 5.29 Impact Factor