Quantitative phosphoproteomics uncovers dysregulated kinase networks in Alzheimer’s disease

Alzheimer’s disease (AD) is a form of dementia characterized by amyloid-β plaques and tau neurofibrillary tangles that progressively disrupt neural circuits in the brain. The signaling networks underlying AD pathological changes are poorly characterized at the phosphoproteome level. Using mass spectrometry, we analyzed the proteome and tyrosine, serine and threonine phosphoproteomes of temporal cortex tissue from patients with AD and aged-matched controls. We identified cocorrelated peptide clusters that were linked to varying levels of phospho-tau, oligodendrocyte, astrocyte, microglia and neuron pathologies. We found that neuronal synaptic protein abundances were strongly anti-correlated with markers of microglial reactivity. We also observed that phosphorylation sites on kinases targeting tau and other new signaling factors were correlated with these peptide modules. Finally, we used data-driven statistical modeling to identify individual peptides and peptide clusters that were predictive of AD histopathologies. Together, these results build a map of pathology-associated phosphorylation signaling events occurring in AD.