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We report that moderately increased concentrations of serum total homocysteine in Alzheimer's disease are associated with the expression of cyclin E (a marker of entry into the cell division cycle) in neurons of the hippocampus. Aberrant entry of neurons into the cell cycle might be an early step in the pathological process.
Expression of proteins related to the control of the cell division cycle has been found in the nuclei of neurons in the cerebral cortex in Alzheimer's disease and it has been proposed that the expression of such proteins, in the absence of cell division, might lead to death of neurons by apoptosis or to the development of neurofibrillary pathology.1 If the aberrant expression of cell cycle markers is part of the pathological process, then it is important to identify possible factors that might trigger the entry of neurons into the cell cycle. Moderately increased concentrations of plasma total homocysteine, an established risk factor for vascular disease,2 are also associated with histopathologically confirmed Alzheimer's disease.3 As in vitro studies have shown that homocysteine can influence the cell cycle in vascular smooth muscle cells and in endothelial cells,4 we wondered whether the expression of cell cycle markers in neurons in Alzheimer's disease might be associated with hyperhomocysteinaemia.
We studied the first 60 patients in the Oxford Project to Investigate Memory and Aging (OPTIMA) where both serum homocysteine and postmortem hippocampal tissue were available. Forty eight patients had a histopathological diagnosis of pure Alzheimer's disease, nine had Alzheimer's disease mixed with vascular pathology and three were controls, without CNS pathology. Total serum homocysteine concentrations were determined in blood samples taken at entry of each patient into the study, on average 29.7 (SD 19) months before death.3 The expression of cyclins B and E was studied by immunohistochemical methods5 in the nuclei of neurons in the hippocampi by an examiner blind to the diagnosis and to the value of serum homocysteine.
Cyclin B expression in neuronal cell nuclei was found in 50 patients with Alzheimer's disease, and cyclin E expression was detected in 27 patients. The concentration of total serum homocysteine in those patients who expressed cyclin B was no different from that in patients who did not express this cyclin. However, the mean concentration of homocysteine in patients who expressed cyclin E in the brain was 18% higher (p<0.045) than that in those who did not express this cyclin (table). Serum vitamin B12 and serum and red blood cell folate concentrations were not significantly different in patients who expressed the cyclins compared with those who did not. To control for the possible influence of other known determinants of serum homocysteine, logistic regression was carried out to see if age, sex, serum creatinine, and serum homocysteine were related to the expression of cyclins B or E. The only significant effect was of homocysteine on expression of cyclin E (p=0.04), which was independent of the other factors.
The cell division cycle is a tightly controlled sequence of events that is driven by the sequential nuclear expression and activation of cyclin and cyclin dependent kinase complexes. The nuclear expression of cyclin E is evidence that the neurons have re-entered the cell division cycle whereas expression of cyclin B indicates progression of the cycle to the G2 phase. We suggest that the association of hyperhomocysteinemia with cyclin E expression, but not with cyclin B expression, may indicate a mitogenic role for homocysteine. The mechanism could be indirect, through the action of homocysteine on the cerebral vasculature, or it might reflect a direct mitogenic action of homocysteine on neurons. Further work is required to test these hypotheses. The rate of atrophy of the hippocampus in Alzheimer's disease is more rapid in patients with increased concentrations of serum homocysteine.3 Thus, if entry into the cell cycle is part of the pathogenic process, then lowering homocysteine concentrations in the blood might slow the progression of the disease.
We thank H Refsum and P Ueland for the homocysteine assays. This work was supported by grants from Bristol-Myers Squibb and Research into Aging.
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