Sequential expression of cell-cycle regulators and Alzheimer's disease-related proteins in entorhinal cortex after hippocampal excitotoxic damage.
Growing evidence suggests that one of the earliest events in the neuronal degeneration of Alzheimer's disease (AD) is aberrant cell-cycle activation in postmitotic neurons, which may, in fact, be sufficient to initiate the neurodegenerative cascade. In the present study we examined whether cyclins and cyclin-dependent kinases, molecules normally associated with cell-cycle control, may be involved in delayed expression of altered Alzheimer's proteins in two interconnected areas, the entorhinal cortex (EC) and the dentate gyrus (DG), after a hippocampal excitotoxic lesion. Several cell-cycle proteins of the G1 and S phases and even of the G2 phase were found to be up-regulated in the EC after kainic acid evoked neuronal death in the hippocampus. In addition, we describe the progressive expression of two Alzheimer's-related proteins, PHF-1 and APP, which reached higher levels immediately after the increase in G1/S-phase markers. Hence, the results of the present study support the participation of cell-cycle dysregulation as a key component of the process that may ultimately lead to expression of AD proteins and neuronal death in a brain area when the target site for synaptic inputs in that area is damaged by an excitotoxic insult.
Hernández-Ortega
Karina
K
Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México.
Ferrera
Patricia
P
Arias
Clorinda
C
D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002453:Cell Cycle; D051360:Cyclin-Dependent Kinase 5 / Q000096:biosynthesis; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis*; D016213:Cyclins / Q000096:biosynthesis*; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D018728:Entorhinal Cortex / Q000378:metabolism* / Q000473:pathology; D000939:Epitopes; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D007608:Kainic Acid; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D016875:tau Proteins / Q000096:biosynthesis*
D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; D015415:Biomarkers; D016213:Cyclins; D000939:Epitopes; D009419:Nerve Tissue Proteins; C085349:PHF-1 monoclonal antibody; C089495:neuronal Cdk5 activator (p25-p35); D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases; D007608:Kainic Acid