Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain.
Alzheimer's disease (AD) is a major dementing illness characterized by regional concentrations of senile plaques, neurofibrillary tangles, and extensive neuronal cell death. Although cell and synaptic loss is most directly linked to the severity of symptoms, the mechanisms leading to the neuronal death remain unclear. Based on evidence linking neuronal death during development to unexpected reappearance of cell cycle events, we investigated the brains of 12 neuropathologically verified cases of Alzheimer's disease and eight age-matched, disease-free controls for the presence of cell cycle proteins. Aberrant expression of cyclin D, cdk4, proliferating cell nuclear antigen, and cyclin B1 were identified in the hippocampus, subiculum, locus coeruleus, and dorsal raphe nuclei, but not inferotemporal cortex or cerebellum of AD cases. With only one exception, control subjects showed no significant expression of cell cycle markers in any of the six regions. We propose that disregulation of various components of the cell cycle is a significant contributor to regionally specific neuronal death in AD.
Busser
J
J
Alzheimer Research Laboratory, Department of Neurology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106, USA.
Geldmacher
D S
DS
Herrup
K
K
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D015415:Biomarkers; D001933:Brain Stem / Q000737:chemistry / Q000166:cytology; D018797:Cell Cycle Proteins / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D019926:Cyclin B / Q000032:analysis / Q000378:metabolism; D056744:Cyclin B1; D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000032:analysis / Q000378:metabolism; D016213:Cyclins / Q000032:analysis / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000737:chemistry / Q000166:cytology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000737:chemistry* / Q000166:cytology* / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis / Q000378:metabolism; D011518:Proto-Oncogene Proteins
D015415:Biomarkers; C534699:CCNB1 protein, human; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D056741:Cyclin D; D016213:Cyclins; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases