Abnormal Expression of the Cell Cycle Regulators P16 and CDK4 in Alzheimer's Disease

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 1997 Jun 1

PMID 9176387

Citations 178

Authors

A McShea

P L Harris

K R Webster

A F Wahl

M A Smith

Affiliations

Soon will be listed here.

Abstract

In this study, we demonstrate that two important regulators of the cell cycle, cyclin-dependent kinase-4 and its inhibitor p16, are increased in the brains of cases of Alzheimer's disease patients compared with age-matched controls. Both proteins are increased in the pyramidal neurons of the hippocampus, including those neurons containing neurofibrillary tangles and granulovacuolar degeneration. As p16 is not normally found in terminally differentiated neurons, it seems paradoxical that it is increased in Alzheimer's disease unless it is responding to increases in cyclin-dependent kinase-4 or other cell cycle regulators. Induction of the latter, a protein that signals re-entry and progression through the cell cycle, may itself be the consequence of alpha response to a growth stimulus. Re-entry into the cell cycle is likely deleterious in terminally differentiated neurons and may contribute to the biochemical abnormalities, such as oxidative stress and hyperphosphorylated tau protein, as well as the neuronal degeneration characteristic of the pathology of Alzheimer's disease.

Citing Articles

Aging and injury drive neuronal senescence in the dorsal root ganglia.

Donovan L, Brewer C, Bond S, Lopez A, Hansen L, Jordan C bioRxiv. 2025; .

PMID: 39829815 PMC: 11741248. DOI: 10.1101/2024.01.20.576299.

Cyclin-dependent protein kinases and cell cycle regulation in biology and disease.

Pellarin I, DallAcqua A, Favero A, Segatto I, Rossi V, Crestan N Signal Transduct Target Ther. 2025; 10(1):11.

PMID: 39800748 PMC: 11734941. DOI: 10.1038/s41392-024-02080-z.

DMRIntTk: Integrating different DMR sets based on density peak clustering.

Zhang W, Jie W, Cui W, Duan G, Zou Y, Peng X PLoS One. 2024; 19(12):e0315920.

PMID: 39715163 PMC: 11666043. DOI: 10.1371/journal.pone.0315920.

Molecular and Cellular Foundations of Aging of the Brain: Anti-aging Strategies in Alzheimer's Disease.

Dziewa M, Zlotek M, Herbet M, Piatkowska-Chmiel I Cell Mol Neurobiol. 2024; 44(1):80.

PMID: 39607636 PMC: 11604688. DOI: 10.1007/s10571-024-01514-0.

Therapeutic targeting of senescent cells in the CNS.

Riessland M, Ximerakis M, Jarjour A, Zhang B, Orr M Nat Rev Drug Discov. 2024; 23(11):817-837.

PMID: 39349637 DOI: 10.1038/s41573-024-01033-z.

References

Ferrari G, Yan C, Greene L . N-acetylcysteine (D- and L-stereoisomers) prevents apoptotic death of neuronal cells. J Neurosci. 1995; 15(4):2857-66. PMC: 6577755. View

Wilhide C, Van Dang C, DiPersio J, Kenedy A, Bray P . Overexpression of cyclin D1 in the Dami megakaryocytic cell line causes growth arrest. Blood. 1995; 86(1):294-304. View

Curcio F, Ceriello A . Decreased cultured endothelial cell proliferation in high glucose medium is reversed by antioxidants: new insights on the pathophysiological mechanisms of diabetic vascular complications. In Vitro Cell Dev Biol. 1992; 28A(11-12):787-90. DOI: 10.1007/BF02631069. View

Stewart B . Mechanisms of apoptosis: integration of genetic, biochemical, and cellular indicators. J Natl Cancer Inst. 1994; 86(17):1286-96. DOI: 10.1093/jnci/86.17.1286. View

Smith M, Sayre L, Monnier V, Perry G . Radical AGEing in Alzheimer's disease. Trends Neurosci. 1995; 18(4):172-6. DOI: 10.1016/0166-2236(95)93897-7. View

Preuss U, Doring F, Illenberger S, Mandelkow E . Cell cycle-dependent phosphorylation and microtubule binding of tau protein stably transfected into Chinese hamster ovary cells. Mol Biol Cell. 1995; 6(10):1397-410. PMC: 301295. DOI: 10.1091/mbc.6.10.1397. View

Pope W, Lambert M, Leypold B, Seupaul R, Sletten L, KRAFFT G . Microtubule-associated protein tau is hyperphosphorylated during mitosis in the human neuroblastoma cell line SH-SY5Y. Exp Neurol. 1994; 126(2):185-94. DOI: 10.1006/exnr.1994.1057. View

Donaldson K, Goolsby G, Kiener P, Wahl A . Activation of p34cdc2 coincident with taxol-induced apoptosis. Cell Growth Differ. 1994; 5(10):1041-50. View

Khachaturian Z . Diagnosis of Alzheimer's disease. Arch Neurol. 1985; 42(11):1097-105. DOI: 10.1001/archneur.1985.04060100083029. View

10.

Sherr C . D-type cyclins. Trends Biochem Sci. 1995; 20(5):187-90. DOI: 10.1016/s0968-0004(00)89005-2. View

11.

Liu W, Williams R, Hall F, Dickson D, Yen S . Detection of a Cdc2-related kinase associated with Alzheimer paired helical filaments. Am J Pathol. 1995; 146(1):228-38. PMC: 1870752. View

12.

Ledesma M, Correas I, Avila J, Diaz-Nido J . Implication of brain cdc2 and MAP2 kinases in the phosphorylation of tau protein in Alzheimer's disease. FEBS Lett. 1992; 308(2):218-24. DOI: 10.1016/0014-5793(92)81278-t. View

13.

Schang L, Hossain A, Jones C . The latency-related gene of bovine herpesvirus 1 encodes a product which inhibits cell cycle progression. J Virol. 1996; 70(6):3807-14. PMC: 190257. DOI: 10.1128/JVI.70.6.3807-3814.1996. View

14.

Grundke-Iqbal I, Iqbal K, Tung Y, Quinlan M, Wisniewski H, Binder L . Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986; 83(13):4913-7. PMC: 323854. DOI: 10.1073/pnas.83.13.4913. View

15.

Dobashi Y, Kudoh T, Toyoshima K, Akiyama T . Persistent activation of CDK4 during neuronal differentiation of rat pheochromocytoma PC12 cells. Biochem Biophys Res Commun. 1996; 221(2):351-5. DOI: 10.1006/bbrc.1996.0599. View

16.

Vincent I, Rosado M, Davies P . Mitotic mechanisms in Alzheimer's disease?. J Cell Biol. 1996; 132(3):413-25. PMC: 2120731. DOI: 10.1083/jcb.132.3.413. View

17.

Spana C, ORourke E, Bolen J, Fargnoli J . Analysis of the tyrosine protein kinase p56lck expressed as a glutathione S-transferase fusion protein in Spodoptera frugiperda cells. Protein Expr Purif. 1993; 4(5):390-7. DOI: 10.1006/prep.1993.1051. View

18.

Brion J, Octave J, Couck A . Distribution of the phosphorylated microtubule-associated protein tau in developing cortical neurons. Neuroscience. 1994; 63(3):895-909. DOI: 10.1016/0306-4522(94)90533-9. View

19.

Olson L . NGF and the treatment of Alzheimer's disease. Exp Neurol. 1993; 124(1):5-15. DOI: 10.1006/exnr.1993.1167. View

20.

Yan G, Ziff E . NGF regulates the PC12 cell cycle machinery through specific inhibition of the Cdk kinases and induction of cyclin D1. J Neurosci. 1995; 15(9):6200-12. PMC: 6577654. View