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Cell Cycle Proteins in Brain in Mild Cognitive Impairment: Insights into Progression to Alzheimer Disease

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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.

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Abbreviations

MCI:

Mild cognitive impairment

aMCI:

Amnestic MCI

AD:

Alzheimer’s disease

NFTs:

Include amyloid beta plaques, neurofibrillary tangles

aβ:

Amyloid beta peptide

APP:

Amyloid precursor protein

LRP1:

Low density lipoprotein receptor-related protein 1

ATP:

Adenosine triphosphate

Pin1:

Peptidyl prolyl cis–trans isomerase

GSK3-β:

Glycogen synthase kinase 3-beta

PP2A:

Protein phosphatase 2A

M:

Mitotic

S:

Synthesis

G:

Gap

CDK:

Cyclin-dependent kinase

CKI:

Cyclin-dependent kinase inhibitor

Rb:

Retinoblastoma protein

VZ:

Ventricular zone

SVZ:

Subventricular zone

CNS:

Central nervous system

E2F1:

E2F transcription factor 1

DP1:

Dimerization partner 1

INK4:

Inhibitors of CDK4

CAK:

CDK-activating kinase

cdc:

Cell division control

Cip/Kip:

CDK interacting protein/Kinase inhibitory protein

MAT1:

Methionine adenosyltransferase 1

IPL:

Inferior parietal lobule

BRCA1:

Breast cancer type 1 susceptibility protein

PM:

Plasma membrane

Wee1:

Ser/Thr family nuclear kinase

P3:

Harmless soluble N-terminal fragment of APP

p53:

Tumor suppressor protein 53

p21:

CIP1/WAF1 cyclin-dependent kinase inhibitor

Mdm2:

Murine double minute oncogene

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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].

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Authors and Affiliations

  1. Department of Chemistry, Center for Membrane Sciences, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, 40506, USA

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

  2. Department of Biochemical Sciences, Sapienza University of Rome, 00185, Rome, Italy

    Ada Fiorini & Marzia Perluigi

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  1. Jeriel T. R. Keeney
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  2. Aaron M. Swomley
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  8. D. Allan Butterfield
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Correspondence to D. Allan Butterfield.

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Keeney, J.T.R., Swomley, A.M., Harris, J.L. et al. Cell Cycle Proteins in Brain in Mild Cognitive Impairment: Insights into Progression to Alzheimer Disease. Neurotox Res 22, 220–230 (2012). https://doi.org/10.1007/s12640-011-9287-2

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  • DOI: https://doi.org/10.1007/s12640-011-9287-2

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