Time-Course Global Proteome Analyses Reveal An Inverse Correlation Between A Beta Burden And Immunoglobulin M Levels In The App(Nl-F) Mouse Model Of Alzheimer Disease

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 beta peptides (A beta), the main constituent of amyloid plaques. To identify A beta-dependent changes to the global proteome we used the recently introduced APP(NL-F) mouse model of AD, which faithfully recapitulates the A beta 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 A beta 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 APP(NL-F/NL-F) mice, relative to APP(NL-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 APP(NL-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 A beta 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.