Cell cycle proteins in brain in mild cognitive impairment: Insights into progression to Alzheimer disease

Jeriel T.R. Keeney, Aaron M. Swomley, Jessica L. Harris, Ada Fiorini, Mihail I. Mitov, Marzia Perluigi, Rukhsana Sultana, D. Allan Butterfield

Research output: Contribution to journalReview articlepeer-review

49 Scopus citations

Abstract

Recent studies have demonstrated the re-emergence of cell cycle proteins in brain as patients progress from the early stages of mild cognitive impairment (MCI) into Alzheimer's disease (AD). Oxidative stress markers present in AD have also been shown to be present in MCI brain suggesting that these events occur in early stages of the disease. The levels of key cell cycle proteins, such as CDK2, CDK5, cyclin G1, and BRAC1 have all been found to be elevated in MCI brain compared to age-matched control. Further, peptidyl prolyl cis-trans isomerase (Pin1), a protein that plays an important role in regulating the activity of key proteins, such as CDK5, GSK3-β, and PP2A that are involved in both the phosphorylation state of Tau and in the cell cycle, has been found to be oxidatively modified and downregulated in both AD and MCI brain. Hyperphosphorylation of Tau then results in synapse loss and the characteristic Tau aggregation as neurofibrillary tangles, an AD hallmark. In this review, we summarized the role of cell cycle dysregulation in the progression of disease from MCI to AD. Based on the current literature, it is tempting to speculate that a combination of oxidative stress and cell cycle dysfunction conceivably leads to neurodegeneration.

Original languageEnglish
Pages (from-to)220-230
Number of pages11
JournalNeurotoxicity Research
Volume22
Issue number3
DOIs
StatePublished - Oct 2012

Bibliographical note

Funding Information:
Acknowledgments This study is dedicated to the outstanding research contribution by Mark A. Smith, a good friend who will be sorely missed, and is supported in part by a NIH grant to D.A.B. [AG-05119].

Keywords

  • APP
  • Alzheimer's disease
  • Amyloid beta-peptide
  • BRCA1
  • CDK5
  • Cell cycle
  • Cyclin G1
  • GSK3-β
  • Kinase
  • Mild cognitive impairment
  • Oxidative stress
  • PP2A
  • Phosphatase
  • Pin1
  • Tau

ASJC Scopus subject areas

  • General Neuroscience
  • Toxicology

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