Fig. 7: MS1262 treatment reversed expression or phosphorylation of protein markers of AD risk or early AD stage.

A Heatmap of select AD-risk markers showing patient-correlated protein expression in the hippocampus of 5x-FAD & APP^NLGF mice whose expression was reversed following MS1262 treatment. Global proteomics data from three age-matched wild-type controls (WT), four 5x-FAD/APP^NLGF mice at mid-/late-stage Alzheimer’s (AD), and four AD mice treated with MS1262 (AD-tr), with each sample run in quadruplicate. Rows are clustered into three groups based on pattern of inhibitor effect: (1) “down_up” = markers down in AD mice, compared to WT controls, whose expression is back up following MS1262 treatment, (2) “up_down” = markers whose expression increases in AD mice, compared to WT controls, but is back down upon treatment, and (3) “not_affected” = inhibitor did not affect expression of these markers. The left annotation column (mouse_model) shows the proteomics dataset (orange = 5x-FAD, green = APP^NLGF) a marker belongs to. Right annotation columns [log2(AD/WT) & log2(AD-tr/AD)] show fold change for indicated comparisons. Rightmost heatmap shows AD-marker expression in 39 patients from the Banner Sun cohort (LPC = 12, HPC = 6, MCI = 6, and AD = 15) that were pooled and measured in duplicate using TMT-LC-MS/MS. LPC = controls with low pathology of plaques and tangles; HPC = controls with high Aβ pathology but no detectable cognitive defects; MCI = mild cognitive impairment with Aβ pathology and a slight but measurable defect in cognition; AD = late-stage AD with high pathology scores of plaques and tangles; FC = fold change. B MS1262 reversed cerebrospinal fluid (CSF) proteome of early-stage AD. Heatmap showing AD markers (identified from CSF of symptomatic/non-symptomatic AD patients) dysregulated in 5xFAD and APP^NLFG mice, compared to DMSO treated wild-type controls, whose expression is reversed following MS1262 treatment. The annotation column on right indicates ‘up’ (red) or ‘down’ (blue) regulation of said marker in symptomatic AD patients compared to age matched non-symptomatic patients. Protein names highlighted in red have AD-dysregulated and G9a reversed expression pattern that shows mouse-to-human conservation. (see also Data S1F).