Increased p27, an essential component of cell cycle control, in Alzheimer's disease

• Published in: Aging cell 2003-04, Vol.2 (2), p.105-110
• Main Authors: Ogawa, Osamu, Lee, Hyoung‐gon, Zhu, Xiongwei, Raina, Arun, Harris, Peggy L. R., Castellani, Rudolph J., Perry, George, Smith, Mark A.
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Cell Cycle; Cell Cycle Proteins - physiology; Cyclin-Dependent Kinase Inhibitor p27; cyclin‐dependent kinase inhibitor; Cytoplasm - chemistry; Female; Hippocampus - pathology; Humans; Male; Mitosis; Nerve Degeneration; Nerve Tissue Proteins - physiology; Neurites - chemistry; Neurofibrillary Tangles - chemistry; Neuropil - chemistry; p27; Phosphorylation; Phosphothreonine - analysis; Protein Processing, Post-Translational; Protein Transport; Protein-Serine-Threonine Kinases - metabolism; Pyramidal Cells - metabolism; Pyramidal Cells - pathology; tau Proteins - analysis; Temporal Lobe - pathology; Tumor Suppressor Proteins - physiology
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1046/j.1474-9728.2003.00042.x

Summary A number of recent findings have demonstrated re‐expression of cell cycle‐related proteins in vulnerable neurones in Alzheimer's disease. We hypothesize that this attempt by neurones to re‐enter mitosis is a response to external growth stimuli that leads to an abortive re‐entry into the cell cycle and, ultimately, neuronal degeneration. In this study, to further delineate the role of mitotic processes in the pathogenesis of Alzheimer's disease, we investigated p27, a cyclin‐dependent kinase inhibitor that plays a negatively regulatory role in cell cycle progression that, once phosphorylated at Thr187, is degraded via an ubiquitin‐proteasome pathway. Here we report that both p27 and phosphorylated p27 (Thr187) show increases in the cytoplasm of vulnerable neuronal populations in Alzheimer's disease vs. age‐matched control subjects. Importantly, phosphorylated p27 (Thr187) shows considerable overlap with tau‐positive neurofibrillary pathology, including neurofibrillary tangles, dystrophic neurites and neuropil threads. The findings presented here suggest that dysregulation of the cell cycle plays a crucial role in the pathogenesis of Alzheimer's disease that may provide a novel mechanistic basis for therapeutic intervention.