Alzheimer’s disease (AD) constitutes one of the leading causes of disability with enormous socioeconomic costs. Most of AD cases occur sporadically and have unknown etiology (SAD). The Abeta peptide deposition in neuritic plaques is one of AD major hallmarks. Nevertheless, the role of Abeta as a primary driver in AD progression arouses controversy. Mounting evidence suggests that neurodegeneration results from the cell cycle reentry occurring in AD neurons. Recent data indicate that some of the cell cycle changes can be also observed in peripheral cells. Thus, our aim was to investigate whether any cell cycle abnormalities occur in transcriptome or proteome of lymphocytes from SAD patients. This study was performed in immortalized lymphocytes from 18 SAD patients and 26 healthy age-matched individuals. PCR arrays experiments showed that 43% of the 90 investigated cell cycle genes were down-regulated in SAD, whereas 4% were up-regulated comparing to control lymphocytes. Since most significant changes referred to the genes engaged in G1/S control, we assessed the levels of key proteins involved in G1/S transition with immunobloting. The most striking difference occurred in p21 protein level, which was significantly elevated for SAD in respect to controls. Furthermore, we measured distribution of cells in G1, S and G2/M cell cycle phases using flow cytometry. Our results showed increased % of cells in G1 phase with adequate decrease in % of cells in S phase for SAD lymphocytes. However, estimation of proliferation rate for SAD and control lymphocytes revealed no significant differences. We therefore used the following methods to assess the lengths of G1 and S phases: flow cytometry analysis of PI-labeled cells after nocodazole treatment and BrdU pulse chase labeling. SAD lymphocytes indicated significant prolongation of G1 phase and simultaneous shortening of S phase. In addition, treating the cells with gamma-secretase inhibitor L685,458 did not affect the observed cell cycle dysregulations, which highlighted that the impairments of cell cycle in SAD lymphocytes are not linked to gamma-secretase activity. Taken together, this study emphasizes that disturbances in the cell cycle control are common for AD neurons as well as SAD lymphocytes. Thus, human lymphocytes could be used in further studies on AD pathogenesis and diagnostics
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