Monoclonal antibodies that target pathological assemblies of Aβ

Northwestern University, Evanston, Illinois, United States
Journal of Neurochemistry (Impact Factor: 4.28). 02/2007; 100(1):23-35. DOI: 10.1111/j.1471-4159.2006.04157.x
Source: PubMed


Amyloid beta (Abeta) immunotherapy for Alzheimer's disease has shown initial success in mouse models of Alzheimer's disease and in human patients. However, because of meningoencephalitis in clinical trials of active vaccination, approaches using therapeutic antibodies may be preferred. As a novel antigen to generate monoclonal antibodies, the current study has used Abeta oligomers (amyloid beta-derived diffusible ligands, ADDLs), pathological assemblies known to accumulate in Alzheimer's disease brain. Clones were selected for the ability to discriminate Alzheimer's disease from control brains in extracts and tissue sections. These antibodies recognized Abeta oligomers and fibrils but not the physiologically prevalent Abeta monomer. Discrimination derived from an epitope found in assemblies of Abeta1-28 and ADDLs but not in other sequences, including Abeta1-40. Immunoneutralization experiments showed that toxicity and attachment of ADDLs to synapses in culture could be prevented. ADDL-induced reactive oxygen species (ROS) generation was also inhibited, establishing this response to be oligomer-dependent. Inhibition occurred whether ADDLs were prepared in vitro or obtained from Alzheimer's disease brain. As conformationally sensitive monoclonal antibodies that selectively immunoneutralize binding and function of pathological Abeta assemblies, these antibodies provide tools by which pathological Abeta assemblies from Alzheimer's disease brain might be isolated and evaluated, as well as offering a valuable prototype for new antibodies useful for Alzheimer's disease therapeutics.

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    • "As a result, there are hundreds of polyclonal and monoclonal A antibodies in use today. Many of these antibodies are reported to be A sequence specific234because they recognize specific peptide segments of A. Other antibodies recognize generic conformational epitopes that are specific to a particular aggregation state, but are independent of the specific aggregated sequence567891011. For example , A11 polyclonal antibodies specifically recognize antiparallel -sheet A prefibrillar oligomers (PFOs), along with PFOs of other amyloid peptides sharing a common generic epitope arising from antiparallel -sheet aggregates[5,12]. "
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    ABSTRACT: Recently we reported that several monoclonal antibodies that recognize linear segments of amyloid-β (Aβ) also recognize amyloid fibrils, but not monomers of unrelated sequences, indicating that recognition of a linear sequence segment is not a reliable indicator of sequence specificity. We asked whether any of the commonly used commercially available Aβ antibodies also recognize fibrils of unrelated sequence. Here we report that 4G8, which recognizes residues 18-23 of the Aβ sequence and is widely believed to be sequence-specific, also recognizes fibrils formed from α-synuclein and islet amyloid polypeptide (IAPP). The recognition of amyloid fibrils is aggregation-dependent because 4G8 does not recognize α-synuclein or IAPP monomer. 4G8 also stains fibrillar α-synuclein aggregates in human multiple system atrophy brain where it colocalizes with anti-α-synuclein monoclonal antibody LB509 immunoreactivity. We also found that LB509 recognizes Aβ fibrils, but not monomer, indicating that generic epitope-reactive antibodies are also produced in response to α-synuclein immunization. Taken together, our results indicate that generic fibril conformational epitope specificity may be a pervasive property among monoclonal antibodies raised against amyloid-forming antigens and that the specificity of their immunoreactivity should be rigorously established and otherwise interpreted with caution.
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    • "ADDLs were shown to inhibit LTP and to promote cell death in a Fyn-dependent mechanism (Lambert et al., 1998). AβOs (more generally referred to as AβOs) are increased in AD brain extracts (Walsh et al., 2002; Gong et al., 2003; Kayed et al., 2003; Lacor et al., 2004; Townsend et al., 2006; Klyubin et al., 2008; Shankar et al., 2009; Xia et al., 2009) and can be detected using oligomersensitive antibodies (Lambert et al., 2001, 2007; Kayed et al., 2003; Rasool et al., 2013), but are not detected by conventional histopathological techniques, such as staining with Thioflavin S or Congo Red. Soon after their identification, oligomers were incorporated into a revised version of the amyloid cascade hypothesis (Klein et al., 2001; Hardy and Selkoe, 2002; Selkoe, 2002a), which posited that soluble AβOs, rather than insoluble fibrils or plaques, would trigger synapse failure and memory impairment. "
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    ABSTRACT: Alzheimer’s disease (AD) is the most common form of dementia in the elderly, and affects millions of people worldwide. As the number of AD cases continues to increase in both developed and developing countries, finding therapies that effectively halt or reverse disease progression constitutes a major research and public health challenge. Since the identification of the amyloid-b peptide (Ab) as the major component of the amyloid plaques that are characteristically found in AD brains, a major effort has aimed to determine whether and how Ab leads to memory loss and cognitive impairment. A large body of evidence accumulated in the past 15 years supports a pivotal role of soluble Ab oligomers (AbOs) in synapse failure and neuronal dysfunction in AD. Nonetheless, a number of basic questions, including the exact molecular composition of the synaptotoxic oligomers, the identity of the receptor(s) to which they bind, and the signaling pathways that ultimately lead to synapse failure, remain to be definitively answered. Here, we discuss recent advances that have illuminated our understanding of the chemical nature of the toxic species and the deleterious impact they have on synapses, and have culminated in the proposal of an Ab oligomer hypothesis for Alzheimer’s pathogenesis. We also highlight outstanding questions and challenges in AD research that should be addressed to allow translation of research findings into effective AD therapies.
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    • "A number of structural and biophysical properties are shared between Ab and tau oligomers, like a high b sheet content, neuronal toxicity, and imperviousness to proteolytic degradation . A limited number of studies using antibodies that specifically target Ab oligomers reflect the potentially powerful role of this approach and warrant further attention (Lambert et al., 2007, 2009; Lee et al., 2006; Mamikonyan et al., 2007; Moretto et al., 2007; Rasool et al., 2013). Another benefit of targeting only the oligomeric form of Ab or tau is that the normal physiological function of these proteins remains intact. "
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