Overexpression of Cell Cycle Proteins of Peripheral Lymphocytes in Patients with Alzheimer's Disease

OBJECTIVE: Biological markers for Alzheimer's disease (AD) will help clinicians make objective diagnoses early during the course of dementia. Previous studies have suggested that cell cycle dysregulation begins earlier than the onset of clinical manifestations in AD. METHODS: We examined the lymphocyte expression of cell cycle proteins in AD patients, dementia controls (DC), and normal controls (NC). One-hundred seventeen subjects (36 AD, 31 DC, and 50 NC) were recruited. The cell cycle proteins CDK2, CDK4, CDK6, cyclin B, and cyclin D were measured in peripheral lymphocytes. Cell cycle protein expression in the three groups was compared after adjusting for age and sex. RESULTS: The levels of cell cycle proteins CDK2, CDK4, CDK6, cyclin B, and cyclin D were significantly higher in AD patients than in the NC subjects. The DC group manifested intermediate levels of cell cycle proteins compared with the AD patients and the NC subjects. The present study indicates that cell cycle proteins are upregulated in the peripheral lymphocytes of AD patients. CONCLUSION: Cell cycle dysregulation in peripheral lymphocytes may present a promising starting point for identifying peripheral biomarkers of AD.

G1/S Cell Cycle Checkpoint Defect in Lymphocytes from Patients with Alzheimer's Disease

OBJECTIVE: We compared the cell responsiveness of activated lymphocytes to rapamycin, which blocks the G1/S transition, between patients with Alzheimer's disease (AD) and normal controls to assess the early phase control defect in cell cycle. METHODS: Blood samples of 26 patients with AD and 28 normal controls were collected to separate peripheral lymphocytes. We measured the proportion of each cell cycle phase in activated lymphocytes using flow cytometry and evaluated the responsiveness of these lymphocytes to rapamycin. RESULTS: The patients with AD were older than the normal controls (AD 74.03+/-7.90 yr vs. control 68.28+/-6.21 yr, p=0.004). The proportion of G1 phase cells in the AD group was significantly lower than that in the control group (70.29+/-6.32% vs. 76.03+/-9.05%, p=0.01), and the proportion of S phase cells in the AD group was higher than that in control group (12.45+/-6.09% vs. 6.03+/-5.11%, p=0.001). Activated lymphocytes in patients with AD were not arrested in the G1 phase and they progressed to the late phase of the cell cycle despite rapamycin treatment, in contrast to those of normal subjects. CONCLUSION: The patients with AD probably have a control defect of early phase cell cycle in peripheral lymphocytes that may be associated with the underlying pathology of neuronal death.

Altered Cell Viability and Proliferation Activity of Peripheral Lymphocytes in Patients with Alzheimer's Disease

OBJECTIVE: We evaluated cell viability and proliferation activity of peripheral lymphocytes as potential models of neuronal death in Alzheimer's disease (AD). METHODS: We analyzed the cell viability and proliferation activity of phytohemagglutinin (PHA)-activated lymphocytes from 68 AD patients and 33 normal controls. The cellular measures were made at baseline (0 hr), 24 hrs, 48 hrs, 72 hrs, and 96 hrs after PHA stimulation. RESULTS: Cell viability in the AD patients was significantly decreased at 72 hrs and 96 hrs, compared with the normal controls. The declining ramp of the proliferation activity from 48 hrs to 72 hrs after PHA stimulation was significantly related to cell viability at 72 hrs and at 96 hrs in the AD patients. CONCLUSION: Lymphocytes from patients with AD have altered viability and proliferation characteristics in culture following PHA stimulation. These findings suggest that lymphocytes may be used as a peripheral tissue model of cell cycle dysregulation in AD.

Cell Viability and Proliferation Activity of Peripheral Lymphocytes in Patients with Alzheimer's Disease / 신경정신의학

OBJECTIVES: There are evidences of apoptotic neuronal cell death in Alzheimer's disease (AD). Recent studies suggested AD pathogenesis in the central nervous system as well as in peripheral lymphocytes. The object of this study is to compare the cell viability and the proliferation activity in AD patients with healthy normal control by using peripheral lymphocytes. METHODS: We analyzed the cell viability and the proliferation activity of phytohemagglutinin (PHA)-activated lymphocytes from 73 AD patients and 31 normal contols. The cell viability and the proliferation activity were measured at baseline (T0), 24 hours (T24), 48 hours (T48), 72 hours (T72), 96 hours (T96), by the tryphan blue method and the BrdU proliferation activity method, respectively. RESULTS: The cell viability of PHA-activated peripheral lymphocytes in AD patients was significantly decreased at T72, T96 compared with healthy controls (F=8.034, p<0.001). In AD patients, the decline of proliferation activity appeared in earlier than healthy normal controls. CONCLUSION: This study suggests that there is a decreased cell viability and the proliferation activity of peripheral lymphocytes in AD patients. These finding may be related with the increased apoptosis in Alzheimer's disease.

Dysregulation of Cell Cycle Regulating Proteins in Peripheral Lymphocytes from the Patients with Alzheimer's Disease / 대한정신약물학회지

OBJECTIVE: Extensive neuronal death occurring in the Alzheimer's disease (AD) may be related with the apoptosis. Recent studies have suggested that regulatory failure of cell cycle appeared to be very early event of AD pathogenesis in neuronal cells as well as in peripheral lymphocytes. We compared the change of cyclin dependent kinases (Cdks), which is related with G1/S phase transition in the cell cycle, between AD patients and normal controls using peripheral lymphocytes. METHODS: We obtained Cdks from peripheral lymphocytes of 37 AD patients and 18 age-matched normal subjects. Cells in first culture were considered to be G-zero (G0) cells. We measured Cdk2, Cdk4, and Cdk6 at baseline (T0). Thereafter, we observed Cdks 24 hours later after using PHA (phytohemaglutinin) (N24). Meanwhile, we observed Cdks 24 hours later again with rapamycin treatment (T24). RESULTS: At baseline (T0), Cdk2 and Cdk6 were increased in AD patients compared to the control group (p< 0.001, p=0.038, respectively). Cdk2 was increased in AD patients more than control group after using PHA (T24, p=0.007). After rapamycin treatment for 24 hours (N24), Cdk2, Cdk4, and Cdk6 were increased in the patients compared to the controls (p=0.002, p=0.022, p=0.011, respectively). CONCLUSION: This results showed that the cell cycle regulating proteins in AD patients, which are related with G1/S phase transition, were increased in peripheral lymphocytes compared to those in normal controls. We provide the clue which demonstrate the cell cycle dysregulation in the patients with Alzheimer's disease.