Blood-Borne Amyloid- Dimer Correlates with Clinical Markers of Alzheimer's Disease

Mental Health Research Institute, The University of Melbourne, Parkville, Melbourne, Victoria 3052, Australia.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2010; 30(18):6315-22. DOI: 10.1523/JNEUROSCI.5180-09.2010
Source: PubMed


Alzheimer's disease (AD) is the most common age-related dementia. Unfortunately due to a lack of validated biomarkers definitive diagnosis relies on the histological demonstration of amyloid-beta (Abeta) plaques and tau neurofibrillary tangles. Abeta processing is implicated in AD progression and many therapeutic strategies target various aspects of this biology. While Abeta deposition is the most prominent feature of AD, oligomeric forms of Abeta have been implicated as the toxic species inducing the neuronal dysfunction. Currently there are no methods allowing routine monitoring of levels of such species in living populations. We have used surface enhanced laser desorption ionization time of flight (SELDI-TOF) mass spectrometry incorporating antibody capture to investigate whether the cellular membrane-containing fraction of blood provides a new source of biomarkers. There are significant differences in the mass spectra profiles of AD compared with HC subjects, with significantly higher levels of Abeta monomer and dimer in the blood of AD subjects. Furthermore, levels of these species correlated with clinical markers of AD including brain Abeta burden, cognitive impairment and brain atrophy. These results indicate that fundamental biochemical events relevant to AD can be monitored in blood, and that the species detected may be useful clinical biomarkers for AD.

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Available from: Pierrick Bourgeat, Oct 07, 2015
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    • "Neither monomeric nor fibrillar forms of Aβ appear to be responsible [4], [5]. Rather, a number of studies indicate that oligomeric Aβ is the most potent neurotoxic species in association with AD [6], [7], [8], [9], [10]. For example, oligomeric Aβ reduces neuronal viability approximately 10-fold more efficiently than fibrillar Aβ [11]. "
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    ABSTRACT: Nuclear inclusion a (NIa) of turnip mosaic virus is a cytosolic protease that cleaves amyloid β (Aβ) when heterologously overexpressed. Lentivirus-mediated expression of NIa in the brains of APP(sw)/PS1 mice significantly reduces cerebral Aβ levels and plaque depositions, and improves behavioral deficits. Here, the effects of NIa and neprilysin (NEP), a well-known Aβ-cleaving protease, on oligomeric Aβ-induced cell death were evaluated. NIa cleaved monomeric and oligomeric Aβ at a similar rate, whereas NEP only cleaved monomeric Aβ. Oligomeric Aβ-induced cytotoxicity and mitochondrial dysfunction were significantly ameliorated by NIa, but not by NEP. Endocytosed fluorescently-labeled Aβ localized to mitochondria, and this was significantly reduced by NIa, but not by NEP. These data suggest that NIa may exerts its protective roles by degrading Aβ and thus preventing mitochondrial deposition of Aβ.
    PLoS ONE 06/2014; 9(6):e98650. DOI:10.1371/journal.pone.0098650 · 3.23 Impact Factor
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    • "The recent report that a phase 3 trial of the Ab-specific monoclonal antibody solanezumab produced a small but significant cognitive benefit in patients with mild AD (Doody, 2012, ANA, conference) has made it even more critical to understand the earliest changes in the economy of synaptotoxic Ab oligomers in the brain and biological fluids. A few reports of the detection of apparent Ab oligomers in CSF and plasma have appeared (Fukumoto et al., 2010; Gao et al., 2010; Klyubin et al., 2008; Villemagne et al., 2010); however, the interpretation of these reports has been clouded by failure to define the precise oligomeric unit the assays are detecting, an inability to exclude definitively the detection of Ab monomers, and, in some cases, the lack of validating the assays on natural oligomers in biological samples. "
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    ABSTRACT: Soluble Aβ oligomers contribute importantly to synaptotoxicity in Alzheimer's disease, but their dynamics in vivo remain unclear. Here, we found that soluble Aβ oligomers were sequestered from brain interstitial fluid onto brain membranes much more rapidly than nontoxic monomers and were recovered in part as bound to GM1 ganglioside on membranes. Aβ oligomers bound strongly to GM1 ganglioside, and blocking the sialic acid residue on GM1 decreased oligomer-mediated LTP impairment in mouse hippocampal slices. In a hAPP transgenic mouse model, substantial levels of GM1-bound Aβ42 were recovered from brain membrane fractions. We also detected GM1-bound Aβ in human CSF, and its levels correlated with Aβ42, suggesting its potential as a biomarker of Aβ-related membrane dysfunction. Together, these findings highlight a mechanism whereby hydrophobic Aβ oligomers become sequestered onto GM1 ganglioside and presumably other lipids on neuronal membranes, where they may induce progressive functional and structural changes.
    Neuron 03/2014; 82(2). DOI:10.1016/j.neuron.2014.02.027 · 15.05 Impact Factor
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    • "Amyloid-β is generated by sequential cleavage of APP by β and γ-secretases. However, the likely predominant route of APP processing is via α-secretase [1,2], which not only precludes amyloid-β production but also generates secreted amyloid precursor protein alpha (sAPPα) [3,4]. This molecule interacts with the β-secretase, BACE1, and directly inhibits amyloid-β production [5]. "
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    ABSTRACT: Background Differential processing of the amyloid precursor protein liberates either amyloid-ß, a causative agent of Alzheimer’s disease, or secreted amyloid precursor protein-alpha (sAPPα), which promotes neuroprotection, neurotrophism, neurogenesis and synaptic plasticity. The underlying molecular mechanisms recruited by sAPPα that underpin these considerable cellular effects are not well elucidated. As these effects are enduring, we hypothesised that regulation of gene expression may be of importance and examined temporally specific gene networks and pathways induced by sAPPα in rat hippocampal organotypic slice cultures. Slices were exposed to 1 nM sAPPα or phosphate buffered saline for 15 min, 2 h or 24 h and sAPPα-associated gene expression profiles were produced for each time-point using Affymetrix Rat Gene 1.0 ST arrays (moderated t-test using Limma: p < 0.05, and fold change ± 1.15). Results Treatment of organotypic hippocampal slice cultures with 1 nM sAPPα induced temporally distinct gene expression profiles, including mRNA and microRNA associated with Alzheimer’s disease. Having demonstrated that treatment with human recombinant sAPPα was protective against N-methyl d-aspartate-induced toxicity, we next explored the sAPPα-induced gene expression profiles. Ingenuity Pathway Analysis predicted that short-term exposure to sAPPα elicited a multi-level transcriptional response, including upregulation of immediate early gene transcription factors (AP-1, Egr1), modulation of the chromatin environment, and apparent activation of the constitutive transcription factors CREB and NF-κB. Importantly, dynamic regulation of NF-κB appears to be integral to the transcriptional response across all time-points. In contrast, medium and long exposure to sAPPα resulted in an overall downregulation of gene expression. While these results suggest commonality between sAPPα and our previously reported analysis of plasticity-related gene expression, we found little crossover between these datasets. The gene networks formed following medium and long exposure to sAPPα were associated with inflammatory response, apoptosis, neurogenesis and cell survival; functions likely to be the basis of the neuroprotective effects of sAPPα. Conclusions Our results demonstrate that sAPPα rapidly and persistently regulates gene expression in rat hippocampus. This regulation is multi-level, temporally specific and is likely to underpin the neuroprotective effects of sAPPα.
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