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Alzheimer's Disease Phosphoproteomics Study Uncovers Signaling Abnormalities

NEW YORK – A team led by researchers at the Massachusetts Institute of Technology has completed an extensive phosphoproteomic analysis looking at dysregulated signaling in Alzheimer's disease.

Detailed in a paper published Monday in Nature Aging, the study identified groups of peptides linked to different pathologies associated with Alzheimer's disease and identified phosphorylation patterns that correlated with these peptide groups, allowing them to map protein signaling events to various aspects of Alzheimer's pathology and its progression.

To generate the data, the researchers analyzed brain tissue from 48 subjects, 25 with Alzheimer's and 23 without, by mass spectrometry using tandem mass tagging to quantify relative changes in the proteome and phosphoproteome.

The authors then used clustering analysis to identify co-correlated peptides that were, as they wrote, "regulated similarly across different patient and control tissues." This analysis yielded 100 different clusters, six of which accounted for almost three-quarters of the total variance among the clusters. Those six were the "oligo," "astro," and "micro" clusters, which consist of proteins "primarily expressed in" oligodendrocytes, astrocytes, and microglia; "neuro" and "pneuro," which contain proteins involved in neuronal synaptic signaling; and "tau," which contains microtubule-associated protein tau peptides "that were upregulated in AD patients."

Investigating how the different clusters related to different aspects of Alzheimer's pathology, the researchers found that the tau cluster was the strongest predictor of Alzheimer's status. They also observed that patients could be separated by the presence or absence of the oligo cluster. Patients who were positive for both clusters also exhibited the greatest number of the other pathology clusters, which the researchers suggested might indicate that "Tau+;Oligo− samples may be at an early stage of disease progression, whereas Tau+;Oligo+ samples may be at a late stage with neuronal synaptic degeneration and reactive gliosis in several cell types."

The researchers also observed that while some patients were positive for astro pathology but not micro pathology, none were positive for micro but not astro pathology, indicating that the astro pathology appears to occur "upstream" of the micro pathology.

Additionally, they looked at how protein phosphorylation was linked to the different pathology clusters, finding that phosphosites and changes in phosphorylation were most strongly linked to the tau and oligo clusters, including "a number of signaling factors known to be active in AD." They also identified a number of new kinase phosphosites linked to Alzheimer's pathologies.

Using their data to identify early- versus late-stage Alzheimer's pathologies and the signaling events associated with these respective pathologies could potentially provide insight into new treatments for the disease. "By targeting the signaling events occurring at an early stage of AD, we may be able to delay or prevent disease progression," the authors wrote.

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