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J.Physiol. were killed. Death was selective for subpopulations of vulnerable neurons and was prevented by knockout of Fyn, a protein tyrosine kinase linked to NMDA receptor signaling. Consistent with dependence on YKL-06-061 signal transduction, toxicity required maturation of the hippocampus and association of oligomers with protease-sensitive cell surface toxin receptors. These findings led to a new hypothesis for the role of A in Alzheimers disease, the Memory loss, beginning early in the disease, was attributed to oligomer-induced disruption of synaptic plasticity, with later stages of dementia attributed to oligomer-induced cellular degeneration and death. Based on a central role for impaired signaling, the oligomer hypothesis predicted that early memory loss should be reversible. This prediction was confirmed in the transgenic mouse experiments mentioned above (Dodart et al., 2002; Kotilinek et al., 2002). The impact of oligomers is in harmony with recent findings that clusterin, which prevents amyloid formation and promotes oligomer formation, is an AD risk factor (Harold et al., 2009; Lambert et al., 2009; Thambisetty et al., 2010).The conclusion that A oligomers can be neurologically significant toxins, possibly the most important ones for AD, is now supported by more than a decade of further investigation, with over 1,000 papers addressing the oligomer hypothesis. Clinical relevance: build up of toxic oligomers in AD and AD animal models The oligomer hypothesis evolved from experiments with synthetic preparations applied to experimental models. Its clinical relevance has been established by evidence that equivalent oligomers accumulate in AD-affected human brain and animal AD models. Although oligomers assemble from soluble A monomers, which are abundant in normal brain tissue, their detection proved feasible through development of sensitive, conformation-dependent antibodies. These antibodies target oligomers without binding A monomers (Kayed et al., 2003; Lambert et al., 2007; Lambert et al., 2001). Dot immunoblots of soluble extracts from human brain show major increases in oligomers in AD-affected tissue (Gong et al., 2003; Kayed et al., 2003; Lambert et al., 2001). Immunohistochemistry confirms that oligomers associate with neurons, accumulating very early in disease progression (Lacor et al., 2004), in loci distinct from amyloid deposits (Kayed et al., 2003). Recent studies have shown that oligomers also manifest in the A-related muscle disease inclusion body myositis (Nogalska et al., 2010). Furthermore, oligomers accumulate with age in diseased brain of essentially all tg AD models examined so far, including mouse, rat, and C. elegans (Chang et al., 2003; Kotilinek et al., 2002; Leon et al., 2010; Wu et al., 2006) for reviews of tg models used in AD research, including their limitations, see (Wisniewski and Sigurdsson, 2010) and (Ashe and Zahs, 2010)). Synthetic and brain-derived oligomers appear structurally equivalent, consistent with the ability of conformation sensitive antibodies generated against oligomers formed to bind oligomers formed with dementing action. It was introduced to distinguish toxic oligomers, which are non-fibrillar, from the well-known fibrillar amyloid. By definition, ADDLs and toxic oligomers refer to the same set of pathogenic molecules. Which term is most suitable remains to be settled. It should be noted that oligomers actually had been found in AD brain extracts several years before the discovery of their toxicity (Frackowiak et al., 1994). At first, however, they were considered irrelevant to pathogenesis, regarded only as indicators of ongoing formation of amyloid, which was considered the actual pathogenic culprit. And in fact, not all oligomers are toxic, even those oligomers of a given size. Subtle conformation changes affect toxicity and immunoreactivity (Chromy et al., 2003; Pitt et al., 2009). However, those oligomers that are toxic appear germane to the disease.[PubMed] [Google Scholar]Allain H, Bentue-Ferrer D, Akwa Y. than degeneration. With chronic exposure, neurons ultimately were killed. Death was selective for subpopulations of vulnerable neurons and was prevented by knockout of Fyn, a protein tyrosine kinase linked to NMDA receptor signaling. Consistent with dependence on signal transduction, toxicity required maturation of the hippocampus and association of oligomers with protease-sensitive cell surface toxin receptors. These findings led to a new hypothesis for the role of A in Alzheimers YKL-06-061 disease, YKL-06-061 the Memory loss, beginning early in the disease, was attributed to oligomer-induced disruption of synaptic plasticity, with later stages of dementia attributed to oligomer-induced cellular degeneration and death. Based on a central role for impaired signaling, the oligomer hypothesis predicted that early memory loss should be reversible. This prediction was confirmed in the transgenic mouse experiments mentioned above (Dodart et al., 2002; Kotilinek et al., 2002). The impact of oligomers is in harmony with recent findings that clusterin, which prevents amyloid formation and promotes oligomer formation, is an AD risk factor (Harold Foxd1 et al., 2009; Lambert et al., YKL-06-061 2009; Thambisetty et al., 2010).The conclusion that A oligomers can be neurologically significant toxins, possibly the most important ones for AD, is now supported by more than a decade of further investigation, with over 1,000 papers addressing the oligomer hypothesis. Clinical relevance: build up of harmful oligomers in AD and AD animal models The oligomer hypothesis developed from experiments with synthetic preparations applied to experimental models. Its medical relevance has been established by evidence that equal oligomers accumulate in AD-affected human brain and animal AD models. Although oligomers assemble from soluble A monomers, which are abundant in normal brain cells, their detection proved feasible through development of sensitive, conformation-dependent antibodies. These antibodies target oligomers without binding A monomers (Kayed et al., 2003; Lambert et al., 2007; Lambert et al., 2001). Dot immunoblots of soluble components from human brain show major raises in oligomers in AD-affected cells (Gong et al., 2003; Kayed et al., 2003; Lambert et al., 2001). Immunohistochemistry confirms that oligomers associate with neurons, accumulating very early in disease progression (Lacor et al., 2004), in loci unique from amyloid YKL-06-061 deposits (Kayed et al., 2003). Recent studies have shown that oligomers also manifest in the A-related muscle mass disease inclusion body myositis (Nogalska et al., 2010). Furthermore, oligomers accumulate with age in diseased mind of essentially all tg AD models examined so far, including mouse, rat, and C. elegans (Chang et al., 2003; Kotilinek et al., 2002; Leon et al., 2010; Wu et al., 2006) for evaluations of tg models used in AD study, including their limitations, observe (Wisniewski and Sigurdsson, 2010) and (Ashe and Zahs, 2010)). Synthetic and brain-derived oligomers appear structurally equivalent, consistent with the ability of conformation sensitive antibodies generated against oligomers created to bind oligomers created with dementing action. It was launched to distinguish harmful oligomers, which are non-fibrillar, from your well-known fibrillar amyloid. By definition, ADDLs and harmful oligomers refer to the same set of pathogenic molecules. Which term is definitely most suitable remains to be settled. It should be mentioned that oligomers actually had been found in AD brain extracts several years before the finding of their toxicity (Frackowiak et al., 1994). At first, however, they were regarded as irrelevant to pathogenesis, considered only as signals of ongoing formation of amyloid, which was regarded as the actual pathogenic culprit. And in fact, not all oligomers are harmful, actually those oligomers of a given size. Delicate conformation changes impact toxicity and immunoreactivity (Chromy et al., 2003;.