Passive immunization of murine models of Alzheimer disease amyloidosis reduces amyloid- peptide (A) levels and improves cognitive function. To specifically address the role of A 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 A structures but not full-length amyloid- precursor protein or C-terminal amyloid- precursor protein fragments. NAB61 also recognized a subset of brain A 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 A oligomers as a pathologic substrate for cognitive decline in Alzheimer disease.The A peptide has been hypothesized to cause the pathologic and behavioral manifestations of Alzheimer disease (AD), 3 including synaptic dysfunction and loss, neurofibrillary tangle formation, neuronal degeneration, and impaired memory. A variety of methods designed to inhibit the production or enhance the clearance of A are being developed as potential AD therapies. Indeed, immunization of murine models of A amyloidosis inhibits senile plaque formation and ameliorates associated cognitive impairments (1-6). Despite the development of meningoencephalitis in 6% of individuals immunized with the A 42 peptide during a phase II clinical human trial (7, 8), immunotherapy, especially passive immunization, remains a compelling potential treatment for AD. Interestingly, passive immunization of mouse models of AD-like A plaques has been shown to rapidly reverse learning and memory deficits without affecting A plaque pathology, indicating that neutralization of toxic A species can quickly restore neuronal function in vivo (9, 10).The lack of learning and memory deficits in young APP transgenic mice indicates that monomeric A is not responsible for behavioral impairments in vivo (11,12). Furthermore, levels of soluble monomeric A do not increase with age or with the onset of cognitive defects in transgenic mice (13). Therefore, if A is responsible for learning and memory deficits in vivo, then A must gain one or more of its toxic properties as a function of time. One potential mechanism for this toxic gain of function is a change in the conformation of A such that it exerts its pathologic effects as an oligomeric or fibrillar macromolecule.To specifically target toxic forms of A, we developed a monoclonal antibody named NAB61 that recognizes a pathologic conformation present in A dimers, soluble oligomers, and higher order species of A. Using this antibody, we found that neutralization of pathologic A by passive immunization of transgenic mice resulted in rapid improvement in spatial learning and memory. These results suggest that pathologic A conformers produced in vivo are capable of disrupting neuronal function, and our data h...
The gasket-seal closure is an effective method for achieving watertight closure of the anterior cranial base after endoscopic intradural surgery.
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