Monoclonal antibodies that target pathological assemblies of Aβ

Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA.
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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    • "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.
    Frontiers in Cellular Neuroscience 05/2015; 9. DOI:10.3389/fncel.2015.00191 · 4.29 Impact Factor
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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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    ABSTRACT: Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is an emerging global epidemic. It is characterized by an imbalance between production and clearance of amyloid β (Aβ) and tau proteins. Oligomeric forms of Aβ and tau are believed to be the most toxic. Dramatic results from AD animal models showed great promise for active and passive immune therapies targeting Aβ. However, there is very limited evidence in human studies of the clinical benefits from these approaches. Immunotherapies targeting only tau pathology have had some success but are limited so far to mouse models. The majority of current methods is based on immunological targeting of a self-protein; hence, benefits need to be balanced against risks of stimulating excessive autoimmune toxic inflammation. For greater efficacy the next generation of vaccines needs to focus more on concurrently targeting all the intermediate toxic conformers of oligomeric Aβ and tau species. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 03/2015; 85(6):1162-1176. DOI:10.1016/j.neuron.2014.12.064 · 15.05 Impact Factor
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    • "Ca 2+ elevation impairs BDNF transport | 1059 and Supplemental Video S1). Irreversible AβO binding was confirmed retrospectively by immunocytochemistry (Figure 1A) using an oligomer-specific antibody (NU-4; Lambert et al., 2007). Representative kymographs illustrate differences between BDNF transport in control (vehicle-treated) and AβO-treated neurons (Figure 1, B and C) and are used to calculate vesicle flux, an index of transport (see Materials and Methods for a detailed explanation ). "
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    ABSTRACT: Disruption of fast axonal transport (FAT) and intracellular Ca(2+) dysregulation are early pathological events in Alzheimer's disease (AD). Amyloid-β oligomers (AβOs), a causative agent of AD, impair transport of BDNF independent of tau by non-excitotoxic activation of calcineurin (CaN). Ca(2+)-dependent mechanisms that regulate the onset, severity, and spatiotemporal progression of BDNF transport defects from dendritic and axonal AβO binding sites are unknown. Here, we show that BDNF transport defects in dendrites and axons are induced simultaneously but exhibit different rates of decline. The spatiotemporal progression of FAT impairment correlates with Ca(2+) elevation and CaN activation first in dendrites and subsequently in axons. Although many axonal pathologies have been described in AD, studies have primarily focused only on the dendritic effects of AβOs despite compelling reports of presynaptic AβOs in AD models and patients. Indeed, we observe that dendritic CaN activation converges on Ca(2+) influx through axonal voltage-gated Ca(2+) channels to impair FAT. Finally, FAT defects are prevented by dantrolene, a clinical compound that reduces Ca(2+) release from the ER. This work establishes a novel role for Ca(2+) dysregulation in BDNF transport disruption and tau-independent Aβ toxicity in early AD. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 01/2015; 26(6). DOI:10.1091/mbc.E14-12-1612 · 4.47 Impact Factor
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