Dataset Information

Anti-a? oligomer IgG and surface sialic acid in intravenous immunoglobulin: measurement and correlation with clinical outcomes in Alzheimer's disease treatment.

ABSTRACT: The fraction of IgG antibodies with anti-oligomeric A? affinity and surface sialic acid was compared between Octagam and Gammagard intravenous immunoglobulin (IVIG) using two complementary surface plasmon resonance methods. These comparisons were performed to identify if an elevated fraction existed in Gammagard, which reported small putative benefits in a recent Phase III clinical trial for Alzheimer's Disease. The fraction of anti-oligomeric A? IgG was found to be higher in Octagam, for which no cognitive benefits were reported. The fraction and location of surface-accessible sialic acid in the Fab domain was found to be similar between Gammagard and Octagam. These findings indicate that anti-oligomeric A? IgG and total surface sialic acid alone cannot account for reported clinical differences in the two IVIG products. A combined analysis of sialic acid in anti-oligomeric A? IgG did reveal a notable finding that this subgroup exhibited a high degree of surface sialic acid lacking the conventional ?2,6 linkage. These results demonstrate that the IVIG antibodies used to engage oligomeric A? in both Gammagard and Octagam clinical trials did not possess ?2,6-linked surface sialic acid at the time of administration. Anti-oligomeric A? IgG with ?2,6 linkages remains untested as an AD treatment.

SUBMITTER: Kwon H

PROVIDER: S-EPMC4380445 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Anti-aβ oligomer IgG and surface sialic acid in intravenous immunoglobulin: measurement and correlation with clinical outcomes in Alzheimer's disease treatment.

Kwon Hyewon H Crisostomo Amanda C AC Smalls Hayley Marie HM Finke John M JM

PloS one 20150331 3

The fraction of IgG antibodies with anti-oligomeric Aβ affinity and surface sialic acid was compared between Octagam and Gammagard intravenous immunoglobulin (IVIG) using two complementary surface plasmon resonance methods. These comparisons were performed to identify if an elevated fraction existed in Gammagard, which reported small putative benefits in a recent Phase III clinical trial for Alzheimer's Disease. The fraction of anti-oligomeric Aβ IgG was found to be higher in Octagam, for which ...[more]

PMID: 25826319

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Project description:BackgroundAlzheimer's disease (AD) is characterized by progressive cognitive decline due to accumulating synaptic insults by toxic oligomers of amyloid beta (AβO) and tau (TauO). There is growing consensus that preventing these oligomers from interacting with synapses might be an effective approach to treat AD. However, recent clinical trial failures suggest low effectiveness of targeting Aβ in late-stage AD. Researchers have redirected their attention toward TauO as the levels of this species increase later in disease pathogenesis. Here we show that AβO and TauO differentially target synapses and affect each other's binding dynamics.MethodsBinding of labeled, pre-formed Aβ and tau oligomers onto synaptosomes isolated from the hippocampus and frontal cortex of mouse and postmortem cognitively intact elderly human brains was evaluated using flow-cytometry and western blot analyses. Binding of labeled, pre-formed Aβ and tau oligomers onto mouse primary neurons was assessed using immunofluorescence assay. The synaptic dysfunction was measured by fluorescence analysis of single-synapse long-term potentiation (FASS-LTP) assay.ResultsWe demonstrated that higher TauO concentrations effectively outcompete AβO and become the prevailing synaptic-associated species. Conversely, high concentrations of AβO facilitate synaptic TauO recruitment. Immunofluorescence analyses of mouse primary cortical neurons confirmed differential synaptic binding dynamics of AβO and TauO. Moreover, in vivo experiments using old 3xTgAD mice ICV injected with either AβO or TauO fully supported these findings. Consistent with these observations, FASS-LTP analyses demonstrated that TauO-induced suppression of chemical LTP was exacerbated by AβO. Finally, predigestion with proteinase K abolished the ability of TauO to compete off AβO without affecting the ability of high AβO levels to increase synaptic TauO recruitment. Thus, unlike AβO, TauO effects on synaptosomes are hampered by the absence of protein substrate in the membrane.ConclusionsThese results introduce the concept that TauO become the main synaptotoxic species at late AD, thus supporting the hypothesis that TauO may be the most effective therapeutic target for clinically manifest AD.

Project description:Several mutations conferring protection against Alzheimer's disease (AD) have been described, none as profound as the A673T mutation, where carriers are four times less likely to get AD compared to noncarriers. This mutation results in reduced amyloid beta (Aβ) protein production in vitro and lower lifetime Aβ concentration in carriers. Better understanding of the protective mechanisms of the mutation may provide important insights into AD pathophysiology and identify productive therapeutic intervention strategies for disease modification. Aβ(1-42) protein forms oligomers that bind saturably to a single receptor site on neuronal synapses, initiating the downstream toxicities observed in AD. Decreased formation, toxicity, or stability of soluble Aβ oligomers, or reduction of synaptic binding of these oligomers, may combine with overall lower Aβ concentration to underlie A673T's disease protecting mechanism. To investigate these possibilities, we compared the formation rate of soluble oligomers made from Icelandic A673T mutant and wild type (wt) Aβ(1-42) synthetic protein, the amount and intensity of oligomer bound to mature primary rat hippocampal/cortical neuronal synapses, and the potency of bound oligomers to impact trafficking rate in neurons in vitro using a physiologically relevant oligomer preparation method. At equal protein concentrations, mutant protein forms approximately 50% or fewer oligomers of high molecular weight (>50 kDa) compared to wt protein. Mutant oligomers are twice as potent at altering the cellular vesicle trafficking rate as wt at equivalent concentrations, however, mutant oligomers have a >4-fold lower binding affinity to synaptic receptors (Kd = 1,950 vs. 442 nM). The net effect of these differences is a lower overall toxicity at a given concentration. This study demonstrates for the first time that mutant A673T Aβ oligomers prepared with this method have fundamentally different assembly characteristics and biological impact from wt protein and indicates that its disease protecting mechanism may result primarily from the mutant protein's much lower binding affinity to synaptic receptors. This suggests that therapeutics that effectively reduce oligomer binding to synapses in the brain may be beneficial in AD.

Dataset Information

Anti-a? oligomer IgG and surface sialic acid in intravenous immunoglobulin: measurement and correlation with clinical outcomes in Alzheimer's disease treatment.

Publications

Anti-aβ oligomer IgG and surface sialic acid in intravenous immunoglobulin: measurement and correlation with clinical outcomes in Alzheimer's disease treatment.

Similar Datasets

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