Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer's disease-like neuropathology (original) (raw)
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Proceedings of The National Academy of Sciences, 2003
Transgenic PDAPP mice, which express a disease-linked isoform of the human amyloid precursor protein, exhibit CNS pathology that is similar to Alzheimer's disease. In an age-dependent fashion, the mice develop plaques containing -amyloid peptide (A) and exhibit neuronal dystrophy and synaptic loss. It has been shown in previous studies that pathology can be prevented and even reversed by immunization of the mice with the A peptide. Similar protection could be achieved by passive administration of some but not all monoclonal antibodies against A. In the current studies we sought to define the optimal antibody response for reducing neuropathology. Immune sera with reactivity against different A epitopes and monoclonal antibodies with different isotypes were examined for efficacy both ex vivo and in vivo. The studies showed that: (i) of the purified or elicited antibodies tested, only antibodies against the N-terminal regions of A were able to invoke plaque clearance; (ii) plaque binding correlated with a clearance response and neuronal protection, whereas the ability of antibodies to capture soluble A was not necessarily correlated with efficacy; (iii) the isotype of the antibody dramatically influenced the degree of plaque clearance and neuronal protection; (iv) high affinity of the antibody for Fc receptors on microglial cells seemed more important than high affinity for A itself; and (v) complement activation was not required for plaque clearance. These results indicate that antibody Fc-mediated plaque clearance is a highly efficient and effective process for protection against neuropathology in an animal model of Alzheimer's disease.
Nature Medicine, 2000
One hallmark of Alzheimer disease is the accumulation of amyloid β-peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid β precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms of the human amyloid precursor protein, show many of the pathological features of Alzheimer disease, including extensive deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy 1,2. Active immunization of PDAPP mice with human amyloid β-peptide reduces plaque burden and its associated pathologies 3. Several hypotheses have been proposed regarding the mechanism of this response 4,5. Here we report that peripheral administration of antibodies against amyloid β-peptide, was sufficient to reduce amyloid burden. Despite their relatively modest serum levels, the passively administered antibodies were able to enter the central nervous system, decorate plaques and induce clearance of preexisting amyloid. When examined in an ex vivo assay with sections of PDAPP or Alzheimer disease brain tissue, antibodies against amyloid β-peptide triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation. These results indicate that antibodies can cross the blood-brain barrier to act directly in the central nervous system and should be considered as a therapeutic approach for the treatment of Alzheimer disease and other neurological disorders.
Vaccine, 2002
Previous studies have shown that in various mouse models of Alzheimer's disease (AD), amyloid -protein (A) antibodies generated by A peptide immunization resulted in the prevention of A plaque formation in brains of young mice, decreased A plaque burdens in older mice and improved cognition. The purpose of this study was to optimize A immunization protocols for future trials in transgenic mouse models of AD. The timing and titers of A antibody production, as well as epitope(s) and imunoglobulin isotypes, were compared between two different mouse strains (C57BL/6 and B6D2F1) and five treatment protocols: (1) chronic A nasal administration, (2) repeated A intraperitoneal (i.p.) injection, (3) one i.p. injection followed by chronic A nasal administration, (4) chronic and concurrent A nasal administration + A i.p. injection, and (5) untreated controls. B6D2F1 mice generated A antibodies earlier and in higher quantities than the C57BL/6 mice, indicating that B6D2F1 mice are more responsive to A immunization. For both strains, mice that received the combination of A nasal + A i.p. injection showed the highest antibody titers. Epitope mapping experiments indicated that the mouse anti-A antibodies recognize residues within A1-15. Immunoglobulin isotyping demonstrated that the A antibodies are of the Th-2 anti-inflammatory type, IgG1 and IgG2b, with a few IgM. Currently there is no effective therapy for Alzheimer's disease; thus if A immunization proves effective, it would be a significant step in the prevention and/or treatment of this devastating disease.
Amelioration of amyloid load by anti-Aβ single-chain antibody in Alzheimer mouse model
Biochemical and Biophysical Research Communications, 2006
Parenteral immunization of transgenic mouse models of Alzheimer disease (AD) with synthetic amyloid β-peptide (Aβ) prevented or reduced Aβ deposits and attenuated their memory and learning deficits. A clinical trial of immunization with synthetic Aβ, however, was halted due to brain inflammation, presumably induced by a toxic Aβ, T-cell-and/or Fc-mediated immune response. Another issue relating to such immunizations is that some AD patients may not be able to raise an adequate immune response to Aβ vaccination due to immunological tolerance or age-associated decline. Because peripheral administration of antibodies against Aβ also induced clearance of amyloid plaques in the model mice, injection of humanized Aβ antibodies has been proposed as a possible therapy for AD. By screening a human single-chain antibody (scFv) library for Aβ immunoreactivity, we have isolated a scFv that specifically reacts with oligomeric Aβ as well as amyloid plaques in the brain. The scFv inhibited Aβ amyloid fibril formation and Aβ-mediated cytotoxicity in vitro. We have tested the efficacy of the human scFv in a mouse model of AD (Tg2576 mice). Relative to control mice, injections of the scFv into the brain of Tg2576 mice reduced Aβ deposits. Because scFvs lack the Fc portion of the immunoglobulin molecule, human scFvs against Aβ may be useful to treat AD patients without eliciting brain inflammation.
Immunological Approach for the Treatment of Alzheimer's Disease
Journal of Molecular Neuroscience, 2003
Formation of amyloid β (Aβ) is a complex kinetic and thermodynamic process, dependent on peptidepeptide interactions that may be modulated by other proteins. We found that site-directed antibodies toward peptide (glutamic acid, phenyl alanine, arginine, histidine) EFRH sequences 3-6 of the N-terminal region of beta-amyloid peptide (AβP) suppress in vitro formation of Aβ and dissolve already formed fibrillar amyloid. These so-called chaperone-like properties of monoclonal antibodies led to the development of a new immunological approach toward Alzheimer's disease (AD) treatment. Production and performance of anti-Aβ antibodies into the transgenic mouse model of AD showed that these antibodies may be delivered from the periphery to the central nervous system, preventing the formation of Aβ and dissolving amyloid plaques. Moreover, immunization with Aβ protects transgenic mice from the learning and age-related memory deficits that occur in AD. These data support the hypotheses that AβP plays a central role in AD, and site-directed antibodies that modulate AβP conformation might lead toward immunotherapy of the disease.
Amyloid-β immunisation for Alzheimer's disease
The Lancet Neurology, 2008
Alzheimer's disease is the main cause of dementia in elderly people and is becoming an ever greater problem as societies worldwide age. Treatments that stop or at least effectively modify disease course do not yet exist. In Alzheimer's disease, the conversion of the amyloid-β peptide (Aβ) from a physiological water-soluble monomeric form into neurotoxic oligomeric and fibrillar forms rich in stable β-sheet conformations is an important event. The most toxic forms of Aβ are thought to be oligomers, and dimers might be the smallest neurotoxic species. Numerous immunological approaches that prevent the conversion of the normal precursor protein into pathological forms or that accelerate clearance are in development. More than ten new approaches to active and passive immunotherapy are under investigation in clinical trials with the aim of producing safe methods for immunological therapy and prevention. A delicate balance between immunological clearance of an endogenous protein with acquired toxic properties and the induction of an autoimmune reaction must be found.
The American Journal of Pathology, 2001
Transgenic mice with brain amyloid- (A) plaques immunized with aggregated A1-42 have reduced cerebral amyloid burden. However, the use of A1-42 in humans may not be appropriate because it crosses the blood brain barrier, forms toxic fibrils, and can seed fibril formation. We report that immunization in transgenic APP mice (Tg2576) for 7 months with a soluble nonamyloidogenic, nontoxic A homologous peptide reduced cortical and hippocampal brain amyloid burden by 89% (P ؍ 0.0002) and 81% (P ؍ 0.0001), respectively. Concurrently, brain levels of soluble A1-42 were reduced by 57% (P ؍ 0.0019). Ramified microglia expressing interleukin-1 associated with the A plaques were absent in the immunized mice indicating reduced inflammation in these animals. These promising findings suggest that immunization with nonamyloidogenic A derivatives represents a potentially safer therapeutic approach to reduce amyloid burden in Alzheimer's disease, instead of using toxic A fibrils.