Dual strategy for reduced signal-suppression effects in matrix-assisted laser desorption/ionization mass spectrometry imaging

Rationale The molecular complexity of tissue features several signal-suppression effects which reduce the ionization of analytes significantly and thereby weakens the quality of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) imaging (MALDI imaging). We report a novel approach in MALDI imaging by reducing signal-suppression effects for the analysis of beta-amyloid (A beta) plaques, one pathological hallmark of Alzheimer's disease (AD). Methods We analyzed A beta proteoforms from postmortem AD brains and brains from transgenic mice (APPPS1-21) overexpressing familial AD mutations by combining two techniques: (1) laser capture microdissection (LCM) to accumulate A beta plaques and (2) phosphoric acid (PA) as additive to the super-2,5-dihydroxybenzoic acid matrix. Results LCM and MALDI-MS enabled tandem mass spectrometric fragmentation of stained A beta plaques. PA improved the signal-to-noise (S/N) ratio, especially of the A beta 1-42 peptide, by three-fold compared with the standard matrix additive trifluoroacetic acid. The beneficial effect of the PA matrix additive in MALDI imaging was particularly important for AD brain tissue. We identified several significant differences in A beta plaque composition from AD compared with APPPS1-21, underlining the value of reducing signal-suppressing effects in MALDI imaging. Conclusions We present a novel strategy for overcoming signal-suppression effects in MALDI imaging of A beta proteoforms.