Proteomic Analysis of Superior Frontal Gyrus from Brains of Humans with Mild Cognitive Impairment and Alzheimer's Disease

摘要

A total of 31,888 peptides corresponding to 4,403 proteins were identified from five biological replicates of control, MCI, and AD human brain samples. Significant changes in expression were observed in 342 proteins in AD and 180 proteins in MCI. Both AD and MCI had significant proteins involved in mitochondrial dysfunction and related oxidative phosphorylation as well as EIF2 signaling. Western blot analysis showed increased expression of Aβ in MCI and AD samples, confirming that the data generated reflect APP-related AD pathology. Mass spec analysis also showed increased coverage of the amyloid-β peptide region of APP in MCI and AD samples compared with non-AD samples which corresponds to the increased generation of Aβ peptide in MCI and AD. Decreased phosphorylation of SIRT2 at Serine 368 in AD and MCI was observed. Reduced phosphorylation of SIRT2 has previously been shown in the hippocampus of AD patients, this data provides site-specific information for the decrease in phosphorylation. SIRT2 is phosphorylated by CDK1/cyclin B at the G2/M transition, regulating the delay in cell cycle progression. RICTOR was predicted to be an activated upstream regulator in AD. RICTOR is a part of the mTOR complex that has been suggested to be involved in Aβ oligomer induced neuronal cell cycle re-entry events through the PI3K-Akt-mTOR pathway. Further validation is ongoing in an effort to identify protein biomarkers and pathway signaling changes in MCI and AD brains as well as insight into the mechanisms involved in MCI and AD progression and pathology.