Targeting amyloid-beta peptide (A beta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in A beta precursor protein (APP) transgenic mice
ABSTRACT 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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ABSTRACT: Beta-amyloid (Abeta) has been suggested as a potent neurotoxic agent. The Abeta-targeted immunotherapy aims to clear diffuse amyloid deposits and reverse memory deficits in Alzheimer's disease. We generated a human single chain variable domain antibody fragment (scFv) against Abeta40, termed E3, by screening a phage antibody library. E3 scFv could recognize Abeta in human cerebral cortex. It was able not only to prevent the aggregation of Abeta but also to disrupt the Abeta preexisting fibrils. Moreover, the Abeta toxicity to SK-N-SH cells was attenuated by addition of E3 scFv. Our results indicate that site-directed human scFv might be a potential therapeutic agent for Alzheimer's disease.Life Sciences 07/2008; 82(25-26):1249-55. DOI:10.1016/j.lfs.2008.04.009 · 2.30 Impact Factor
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ABSTRACT: In an effort to identify the factors that are involved in the pathogenesis of Alzheimer's disease (AD), epidemiological studies have featured prominently in contemporary research. Of those epidemiological factors, accumulating evidence implicates traumatic brain injury (TBI) as a possible predisposing factor in AD development. Exactly how TBI triggers the neurodegenerative cascade of events in AD remains controversial. There has been extensive research directed towards understanding the potential relationship between TBI and AD and the putative influence that apolipoprotein E (APOE) genotype has on this relationship. The aim of the current paper is to provide a critical summary of the experimental and human studies regarding the association between TBI, AD and APOE genotype. It will be shown that despite significant discrepancies in the literature, there still appears to be an increasing trend to support the hypothesis that TBI is a potential risk factor for AD. Furthermore, although it is known that APOE genotype plays an important role in AD, its link to a deleterious outcome following TBI remains inconclusive and ambiguous.Progress in brain research 02/2007; 161:303-16. DOI:10.1016/S0079-6123(06)61021-2 · 5.10 Impact Factor
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ABSTRACT: It is now 100 years since the nosological definition of Alzheimer's disease emerged. In the first 80 years, very little progress was made in understanding the mechanisms that caused the brain to degenerate in a remarkably specific fashion (amyloid accumulation with neurofibrillary changes). Over the past 20 years, there has been an explosion of knowledge which continues today at an exponential rate. The molecular pathways underlying the synaptic dysfunction in Alzheimer's disease have delivered many validated therapeutic and diagnostic targets. A variety of therapeutic strategies aimed at disease modification are now in clinical development.Brain 12/2006; 129(Pt 11):2823-39. DOI:10.1093/brain/awl251 · 10.23 Impact Factor