Lee EB, Leng LZ, Zhang B, Kwong L, Trojanowski JQ, Abel T et al. Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Abeta precursor protein (APP) transgenic mice. J Biol Chem 281: 4292-4299

Biology, William Penn University, Filadelfia, Pennsylvania, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2006; 281(7):4292-9. DOI: 10.1074/jbc.M511018200
Source: PubMed


Passive immunization of murine models of Alzheimer disease amyloidosis reduces amyloid-beta peptide (Abeta) levels and improves cognitive function. To specifically address the role of Abeta oligomers in learning and memory, we generated a novel monoclonal antibody, NAB61, that preferentially recognizes a conformational epitope present in dimeric, small oligomeric, and higher order Abeta structures but not full-length amyloid-beta precursor protein or C-terminal amyloid-beta precursor protein fragments. NAB61 also recognized a subset of brain Abeta deposits, preferentially mature senile plaques, and amyloid angiopathy. Using NAB61 as immunotherapy, we showed that aged Tg2576 transgenic mice treated with NAB61 displayed significant improvements in spatial learning and memory relative to control mice. These data implicated Abeta oligomers as a pathologic substrate for cognitive decline in Alzheimer disease.

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    • "A wide variety of such oligomer-specific antibodies is now available. For example, NAB61 is a monoclonal antibody specific for Aβ oligomers developed by synthesizing oligomeric aggregates from nitrated Aβ and using them as antigens [146]. Antibodies NU1, NU2 and NU4 used small β-sheet rich Aβ oligomers as antigens [147] [148] [149]. "
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    ABSTRACT: Protein misfolding and aggregation are known to play a crucial role in a number of important human diseases (Alzheimer's, Parkinson's, prion, diabetes, cataracts, etc.) as well as in a multitude of physiological processes. Protein aggregation is a highly complex process resulting in a variety of aggregates with different structures and morphologies. Oligomeric protein aggregates (amyloid oligomers) are formed as both intermediates and final products of the aggregation process. They are believed to play an important role in many protein aggregation-related diseases, and many of them are highly cytotoxic. Due to their instability and structural heterogeneity, information about structure, mechanism of formation, and physiological effects of amyloid oligomers is sparse. This review attempts to summarize the existing information on the major properties of amyloid oligomers. Copyright © 2015. Published by Elsevier B.V.
    FEBS letters 07/2015; DOI:10.1016/j.febslet.2015.07.013 · 3.17 Impact Factor
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    • "To evaluate the relevance of our findings to AD, we estimated the volume of human cortex occupied by type 2 Abo in AD, using two different methods. One method depended on immunohistological data of tissue stained with the Abo-specific antibody NAB-61 (Lee et al., 2006), which we inferred selectively recognizes type 2 Abo and amyloid fibrils from its almost exclusive staining of neuritic plaques (dense-core plaques associated with neuritic abnormalities [Serrano-Pozo et al., 2011]). The average volume of AD cortex occupied by Ab assemblies detected using NAB-61 was $5% (Perez-Nievas et al., 2013). "
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    ABSTRACT: The accumulation of amyloid-β (Aβ) as amyloid fibrils and toxic oligomers is an important step in the development of Alzheimer's disease (AD). However, there are numerous potentially toxic oligomers and little is known about their neurological effects when generated in the living brain. Here we show that Aβ oligomers can be assigned to one of at least two classes (type 1 and type 2) based on their temporal, spatial, and structural relationships to amyloid fibrils. The type 2 oligomers are related to amyloid fibrils and represent the majority of oligomers generated in vivo, but they remain confined to the vicinity of amyloid plaques and do not impair cognition at levels relevant to AD. Type 1 oligomers are unrelated to amyloid fibrils and may have greater potential to cause global neural dysfunction in AD because they are dispersed. These results refine our understanding of the pathogenicity of Aβ oligomers in vivo. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 06/2015; 11(11). DOI:10.1016/j.celrep.2015.05.021 · 8.36 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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