4.4 Article

Quantitative phosphoproteomics uncovers dysregulated kinase networks in Alzheimer's disease

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NATURE AGING
卷 1, 期 6, 页码 550-+

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SPRINGERNATURE
DOI: 10.1038/s43587-021-00071-1

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资金

  1. NIH Biotechnology Training grant [T32GM008334]
  2. US Army Research Office Cooperative Agreement [W911NF-19-2-0026]
  3. Institute for Collaborative Biotechnologies
  4. National Science Foundation Graduate Research Fellowship Program [1745302]
  5. National Institute of Neurological Disorders and Stroke [U24 NS072026]
  6. National Institute on Aging [P30 AG19610]
  7. Arizona Alzheimer's Disease Core Center
  8. Arizona Department of Health Services [211002]
  9. Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]
  10. Michael J. Fox Foundation for Parkinson's Research

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The study analyzed the proteome and phosphoproteome of brain tissue from Alzheimer's disease patients, uncovering correlations between neuronal synaptic protein abundances, microglial reactivity markers, and phosphorylation sites on kinases targeting tau. This provides insight into pathology-associated phosphorylation signaling events in Alzheimer's disease.
Morshed et al. analyzed the proteome and phosphoproteome of brain tissue from patients with Alzheimer's disease. The analysis of patient heterogeneity links glia pathologies and signaling pathways to stages of disease progression. Alzheimer's disease (AD) is a form of dementia characterized by amyloid-beta 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.

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