Circulating immune complexes of Aβ and IgM in plasma of patients with Alzheimer’s disease

Marcello, Andrea; Wirths, Oliver; Schneider‐Axmann, Thomas; Degerman-Gunnarsson, Malin; Lannfelt, Lars; Bayer, Thomas A.

doi:10.1007/s00702-009-0224-y

Cited by 22 publications

(18 citation statements)

References 58 publications

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“…While these antibodies may play a physiological role, they also pose a challenge for the development of blood-based diagnostics, i.e., unless efforts are undertaken to promote the dissociation of pre-existing Aβ-immunoglobulin complexes [ 32 ], their existence may add to variability in detection results by masking the true levels of Aβ in the blood [ 33 ]. Whereas most previous studies did not specifically investigate interactions between Aβ and IgM, one study documented the existence of IgM-Aβ complexes in blood but did not detect differences between MCI and AD samples [ 34 ]. However, the same authors subsequently reported a reduction of IgM auto-antibodies against pyro-glu Aβ [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Time-course global proteome analyses reveal an inverse correlation between Aβ burden and immunoglobulin M levels in the APPNL-F mouse model of Alzheimer disease

et al. 2017

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Alzheimer disease (AD) stands out amongst highly prevalent diseases because there is no effective treatment nor can the disease be reliably diagnosed at an early stage. A hallmark of AD is the accumulation of aggregation-prone amyloid β peptides (Aβ), the main constituent of amyloid plaques. To identify Aβ-dependent changes to the global proteome we used the recently introduced APPNL-F mouse model of AD, which faithfully recapitulates the Aβ pathology of the disease, and a workflow that interrogated the brain proteome of these mice by quantitative mass spectrometry at three different ages. The elevated Aβ burden in these mice was observed to cause almost no changes to steady-state protein levels of the most abundant >2,500 brain proteins, including 12 proteins encoded by well-confirmed AD risk loci. The notable exception was a striking reduction in immunoglobulin heavy mu chain (IGHM) protein levels in homozygote APPNL-F/NL-F mice, relative to APPNL-F/wt littermates. Follow-up experiments revealed that IGHM levels generally increase with age in this model. Although discovered with brain samples, the relative IGHM depletion in APPNL-F/NL-F mice was validated to manifest systemically in the blood, and did not extend to other blood proteins, including immunoglobulin G. Results presented are consistent with a cause-effect relationship between the excessive accumulation of Aβ and the selective depletion of IGHM levels, which may be of relevance for understanding the etiology of the disease and ongoing efforts to devise blood-based AD diagnostics.

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Section: Discussionmentioning

confidence: 99%

Time-course global proteome analyses reveal an inverse correlation between Aβ burden and immunoglobulin M levels in the APPNL-F mouse model of Alzheimer disease

et al. 2017

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“…Intriguingly, IgM anti-Aβ autoantibodies are found in essentially all individuals, although in different concentrations [17], [18], [23]. These human IgM autoantibodies have previously been studied with the aim of identifying differences between healthy controls and individuals affected by mild cognitive impairment or AD [18], [23]. Differences in IgM auto-antibodies have been suggested as a potential diagnostic marker, as the levels of specific IgM auto-antibodies were lower in AD patients compared to controls [18].…”

Section: Discussionmentioning

confidence: 99%

Amyloid-β Oligomer Specificity Mediated by the IgM Isotype – Implications for a Specific Protective Mechanism Exerted by Endogenous Auto-Antibodies

et al. 2010

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BackgroundAlzheimers disease (AD) has been strongly linked to an anomalous self-assembly of the amyloid-β peptide (Aβ). The correlation between clinical symptoms of AD and Aβ depositions is, however, weak. Instead small and soluble Aβ oligomers are suggested to exert the major pathological effects. In strong support of this notion, immunological targeting of Aβ oligomers in AD mice-models shows that memory impairments can be restored without affecting the total burden of Aβ deposits. Consequently a specific immunological targeting of Aβ oligomers is of high therapeutic interest.Methodology/Principal FindingsPreviously the generation of conformational-dependent oligomer specific anti-Aβ antibodies has been described. However, to avoid the difficult task of identifying a molecular architecture only present on oligomers, we have focused on a more general approach based on the hypothesis that all oligomers expose multiple identical epitopes and therefore would have an increased binding to a multivalent receptor. Using the polyvalent IgM immunoglobulin we have developed a monoclonal anti-Aβ antibody (OMAB). OMAB only demonstrates a weak interaction with Aβ monomers and dimers having fast on and off-rate kinetics. However, as an effect of avidity, its interaction with Aβ-oligomers results in a strong complex with an exceptionally slow off-rate. Through this mechanism a selectivity towards Aβ oligomers is acquired and OMAB fully inhibits the cytotoxic effect exerted by Aβ(1-42) at highly substoichiometric ratios. Anti-Aβ auto-antibodies of IgM isotype are frequently present in the sera of humans. Through a screen of endogenous anti-Aβ IgM auto-antibodies from a group of healthy individuals we show that all displays a preference for oligomeric Aβ.Conclusions/SignificanceTaken together we provide a simple and general mechanism for targeting of oligomers without the requirement of conformational-dependent epitopes. In addition, our results suggest that IgM anti-Aβ auto-antibodies may exert a more specific protective mechanism in vivo than previously anticipated.

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“…However, there appears to be a contribution from nonneuronal tissues and, more important, Aβ is bound to a variety of proteins in blood, and thus should be interpreted with caution when used for diagnosis, as discussed later [39]. …”

Section: Major Challenges In Blood-based Biomarker Development For Admentioning

confidence: 99%

The future of blood‐based biomarkers for Alzheimer's disease

Henriksen

O’Bryant

Hampel

et al. 2013

Alzheimer's & Dementia

277

224

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Treatment of Alzheimer’s disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood-Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood-based biomarkers of AD, including patient heterogeneity, inclusion of the “right” control population, and the blood– brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field.

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Circulating immune complexes of Aβ and IgM in plasma of patients with Alzheimer’s disease

Cited by 22 publications

References 58 publications

Time-course global proteome analyses reveal an inverse correlation between Aβ burden and immunoglobulin M levels in the APPNL-F mouse model of Alzheimer disease

Time-course global proteome analyses reveal an inverse correlation between Aβ burden and immunoglobulin M levels in the APPNL-F mouse model of Alzheimer disease

Amyloid-β Oligomer Specificity Mediated by the IgM Isotype – Implications for a Specific Protective Mechanism Exerted by Endogenous Auto-Antibodies

The future of blood‐based biomarkers for Alzheimer's disease

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