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
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.
"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 . Antibodies NU1, NU2 and NU4 used small β-sheet rich Aβ oligomers as antigens   . "
"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). "
"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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