Increased p27, an essential component of cell cycle control, in Alzheimer's disease.
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.
Ogawa
Osamu
O
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Lee
Hyoung-gon
HG
Zhu
Xiongwei
X
Raina
Arun
A
Harris
Peggy L R
PL
Castellani
Rudolph J
RJ
Perry
George
G
Smith
Mark A
MA
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003593:Cytoplasm / Q000737:chemistry; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008297:Male; D008938:Mitosis; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000502:physiology*; D016501:Neurites / Q000737:chemistry; D016874:Neurofibrillary Tangles / Q000737:chemistry; D019581:Neuropil / Q000737:chemistry; D010766:Phosphorylation; D010769:Phosphothreonine / Q000032:analysis; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D017966:Pyramidal Cells / Q000378:metabolism* / Q000473:pathology; D013702:Temporal Lobe / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D016875:tau Proteins / Q000032:analysis
D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D016875:tau Proteins; D010769:Phosphothreonine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases