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Beyond amyloid:altered cell cycle regulation in Alzheimer's disease:comparison of P21 signaling in patients lymphocytes and brain neurons

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Mietelska-Porowska A., Wojsiat J., Laskowska-Kaszub K., Stepien T., Wierzba-Bobrowicz T., Wojda U.
Acta Neurobiologiae Experimentalis
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2015
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tom 75
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nr Supl.
BACKGROUND AND AIMS: Alzheimer’s disease (AD) develops for decades, but the molecular mechanism of pathogenesis is poorly understood. In result, an effective AD cure is still missing. According to the cell cycle (CC) hypothesis, one of the AD causes is CC reactivation in mature neurons. We aimed at elucidation if similar CC alterations occur in AD brain neurons and in peripheral blood cells. METHODS: As the study materials, we used 40 lines of immortalized lymphoblasts from sporadic AD (SAD) patients and 40 lines from healthy non-demented individuals (controls)1-4. CC in lymphocytes was analyzed by real-time PCR-arrays, immunoblotting, and flow cytometry. Human post mortem brain tissue from AD patients was prepared by paraffin embedding and microscopic tissue slides of hippocampus and enthorinal cortex was analyzed by antip21 immunohistochemical staining. RESULTS: Our data demonstrated aberrant CC in SAD lymphoblasts that involved a prolongation of the G1 phase driven by a marked increase of levels of p21 protein (Walf1/Cip1/Sid1), the key regulator of the G1/S CC checkpoint and of apoptosis. Consistently, we also found differences in p21 levels and its signaling pathway in apoptotic response of SAD lymphoblasts to redox stess. The analysis of p21 protein levels and related signaling in AD brain neurons will also be presented. CONCLUSIONS: In summary, these studies indicate that p21-related molecular changes underlie altered cell cycle and apoptosis in AD pathology and may represent novel therapeutic targets. Moreover, our data show that AD have a features of a systemic disease with CC alterations in peripheral lymphoblasts which thus have a potential diagnostic value. Support: CEPT, Polish National Science Centre grant NN401 596840, and JPND grant 2/BIOMARKAPD/JPND/2012.
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Alterations in apoptotic signaling in lymphocytes of patients in early stage of Alzheimer's disease precede massive neuronal loss in the brain

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Wojsiat J., Laskowska-Kaszub K., Mandecka M., Gabryelewicz T., Kuznicki J., Wojda U.
Acta Neurobiologiae Experimentalis
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2015
|
tom 75
|
nr Supl.
BACKGROUND AND AIMS: Alzheimer’s disease (AD) is the most common age-related dementia worldwide of unclear early pathogenesis. Mild Cognitive Impairment (MCI) represents an early AD stage, preceding massive deposition of Aβ aggregates and associated neuronal loss in the brain. Recently we demonstrated that sporadic AD (SAD) lymphoblasts show increased levels of p21 protein, the key regulator of G1/S cell cycle checkpoint and apoptosis (Bialopiotrowicz et al. 2011, Neurobiol Aging). In the current study we aimed to elucidate if p21 levels are altered early in AD, in lymphocytes of MCI patients, and to investigate the effects of p21 on the apoptotic response of SAD and MCI lymphocytes METHODS: We compared apoptotic response to 2 deoxy-D ribose (2dRib) in EBV-immortalized B-lymphoblasts from 16 patients with SAD, 17 patients with MCI and 10 age-matched healthy individuals without dementia. Apoptotic response was measured using flow cytometry assays: AnnexinV, mitochondrial membrane potential, and SubG1-phase. RESULTS: Comparing to controls, under basal conditions p21 levels assessed by immunoblotting were significantly elevated in MCI lymphoblasts, similarly as in SAD cells. 24 h after 2dRib treatment, apoptosis was higher in SAD cells than in controls, and after stimulation p21 decreased significantly in SAD and MCI cells. CONCLUSIONS: SAD lymphoblasts are significantly lessresistant to oxidative apoptotic stimuli than controls. In MCI lymphoblasts there were similar tendencies but without statistical significance. These results suggest that changes in the p21 levels and in apoptotic response in lymphocytes appear early in AD and gradually increase with the disease progression. Furthermore, our data indicate that lymphocytes may be useful for the development of new early AD diagnostic markers based on apoptotic regulatory proteins such as p21. This research was supported by the grant 2/BIOMARKAPD/ JPND/2012 and by the Nencki Institute statutory funds.
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