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

PLoS One. 2017 Aug 23;12(8):e0182844. doi: 10.1371/journal.pone.0182844. eCollection 2017.

Abstract

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.

MeSH terms

  • Alzheimer Disease / immunology
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Blotting, Western
  • Disease Models, Animal*
  • Electrophoresis, Polyacrylamide Gel
  • Immunoglobulin M / immunology*
  • Mass Spectrometry
  • Mice

Substances

  • Amyloid beta-Peptides
  • Immunoglobulin M

Grants and funding

Work on this project was supported by an operating grant from the Canadian Institute for Health Research (CIHR) to GS, an infrastructure grant from the Canadian Foundation for Innovation to GS, PF and ER, as well as support from the National Institutes of Health to ER. The authors are most grateful to the Irwin family for their continued support and acknowledge a generous gift by the Rosiak family. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.